Elsevier

Clinical Oncology

Volume 19, Issue 2, March 2007, Pages 108-114
Clinical Oncology

Overview
Ifosfamide Encephalopathy

https://doi.org/10.1016/j.clon.2006.11.003Get rights and content

Abstract

Encephalopathy is a potentially fatal toxicity of ifosfamide. Clinical manifestations of encephalopathy range from fatigue and confusion to coma and death. Early identification of this toxicity and prompt cessation of ifosfamide are the essential elements in the management of ifosfamide encephalopathy. Accurate prediction of this toxicity is often difficult. Based on the limited available evidence, methylene blue, an electron acceptor, may have a role in the treatment and the prevention of neurotoxicity. This paper reviews the current understanding of ifosfamide encephalopathy.

Introduction

Ifosfamide, an alkylating agent and isomer of cyclophosphamide, is used as a single agent or a component of multi-agent chemotherapy in the treatment of gynaecological, testicular and head and neck cancers, sarcomas and lymphomas [1]. It also has an established role in the treatment of paediatric malignancies, including neuroblastoma, nephroblastoma, malignant mesenchymal tumours, rhabdomyosarcoma, Ewing's sarcoma and osteosarcoma 2, 3. Ifosfamide is a pro-drug that requires activation by the hepatic microsomal enzymes to ifosforamide mustard. It alkylates DNA, forming DNA–DNA cross-links that result in the inhibition of DNA synthesis and cell death [4]. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity [1]. Neurotoxicity is the dose-limiting toxicity of ifosfamide when preventive measures are taken to reduce nephrotoxicity using mesna (sodium 2-mercaptoethane sulphonate) [4]. Some degree of central nervous system (CNS) toxicity can occur in about 10–30% (mean 12%) of patients after intravenous infusion. The clinical spectrum of this CNS toxicity is wide, ranging from mild somnolence and confusion to severe encephalopathy and coma. The true incidence of severe encephalopathy is unknown. The incidence of CNS toxicity may be increased to 50% after oral administration of ifosfamide because of differences in the preferential route of metabolism between the two routes 5, 6, 7, 8.

Section snippets

Mechanism of Neurotoxicity

Ifosfamide-induced encephalopathy represents a severe adverse effect of unknown origin [9]. The most widely accepted hypothesis is that encephalopathy is produced by one or more of the ifosfamide metabolites, particularly chloroacetaldehyde. Kupfer et al.[9] hypothesised a number of possible pathophysiological pathways for the development of ifosfamide encephalopathy (Fig. 1).

Ifosfamide requires hepatic activation to the cytotoxically active metabolite ifosforamide mustard. During metabolism,

Clinical Features

Encephalopathy occurs most often during, or shortly after, drug administration. The incidence of encephalopathic symptoms varies in different studies. Confusion is the most common symptom, occurring in more than 80% of cases, and ranges from transient lethargy or increased drowsiness to frank delirium. The second most common manifestation is hallucination or psychosis, occurring in up to 30% of patients. Incontinence and muscle twitching are present in about 9% of patients [14]. Less common

Investigations and Diagnosis

Ifosfamide encephalopathy is essentially a clinical diagnosis. It is supported by normal brain imaging, electroencephalogram (EEG) findings of metabolic encephalopathy and the absence of another cause.

Blood investigations may show hypoalbuminaemia, hyponatraemia, hypokalaemia and deranged renal function. Magnetic resonance imaging and computed tomography do not reveal any lesions in encephalopathy 8, 16. However, routine imaging of the brain is not immediately necessary, unless the

Risk Group and Prediction of Toxicity

The reported risk factors for ifosfamide encephalopathy include low serum albumin, elevated serum creatinine, the presence of tumour in the lower abdomen and pelvis, pre-treatment with cisplatin and prior CNS disease 14, 24, 31, 32, 33, 34. Although hypokalaemia and hyponatraemia are reported to be associated with encephalopathy, their potential role as risk factors is not known 27, 35.

Low serum albumin (<35 g/l) seems to be associated with a high risk of severe neurotoxicity (odds ratio 4.3;

Treatment

Ifosfamide encephalopathy usually reverses completely within 1–3 days after the cessation of drug administration 19, 36. Hence, early recognition of this side-effect and prompt cessation of the ifosfamide infusion are the mainstay of management. The correction of any metabolic abnormalities, if present, is also important.

Although published reports supporting treatment modalities such as intravenous albumin, thiamin and methylene blue are minimal (Table 2), methylene blue has been increasingly

Clinical Approach to Patients with Suspected Ifosfamide Encephalopathy

In patients with suspected encephalopathy, the ifosfamide infusion should be stopped immediately and measures should be taken to correct any fluid and electrolyte imbalance. Although there is no convincing evidence that drugs affecting the CNS (narcotic analgesics, benzodiazepines, phenothiazines and metaclopromide) have any influence on the development of encephalopathy, these drugs should be avoided if possible [24]. A detailed clinical examination, including full neurological and higher

Conclusions

Ifosfamide encephalopathy is a potentially fatal toxicity. Early clinical suspicion with prompt cessation of ifosfamide is the corner stone of management. Intravenous methylene blue may either shorten the duration of encephalopathy or sometimes completely reverse symptoms. It may also be used for the prevention of ifosfamide-induced encephalopathy, although data showing clear evidence of efficacy for either treatment or prophylaxis are lacking. Further research is needed to better understand

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