Cancer Res Treat. 2011;43(4):260-263 (Fig. 2) [11,13]. The accumulation of glutaric acid may lead to an increase in chloroethyl amine, the metabolism of which may in turn disturb the mitochondrial respiratory chain. Thus, the accumulation of nicotinamide adenine dinucleotide hydrogen (NADH) may prevent the dehydrogena- tion of aldehydes such as the ifosfamide metabolite CAA, a potentially neurotoxic substance [9]. CAA, which is structurally similar to both chlo- ral hydrate and acetaldehyde, can cross the BBB and therefore be respon- sible for ifosfamide-induced encephalopathy [7]. The neurotoxic effects of CAA may be due to 1) a direct neurotoxic effect, 2) depletion from the CNS of glutathione, and/or 3) the inhibition of mitochondrial oxidative phosphorylation resulting in impaired fatty acid metabolism [2]. CNS toxicity displays a wide spectrum of signs and symptoms. Man- ifestations of ifosfamide-induced encephalopathy include cerebellar ataxia, mental confusion, complex visual hallucinations, extrapyramidal signs, seizures and/or mutism. Less common CNS manifestations of ifos- famide are asterixis, nonconvulsive status epilepticus, manic episodes and cerebellar and temporo-frontal cortical degeneration [6]. According to the National Cancer Institute Toxicity Grading for En- cephalopathy [14], there are five grades of encephalopathy. Most patients with ifosfamide-induced encephalopathy show grade 1 or 2 symptoms. Many patients with ifosfamide-induced encephalopathy recover sponta- neously and completely within 48-72 hours following the onset of dis- continuation of ifosfamide and conservative management such as adequate hydration. Some patients with ifosfamide-induced encephalopa- thy present with grade 3 or 4 symptoms. However, most patients with grade 3 or 4 symptoms can also recover spontaneously and completely. In rare cases, grade 3 or 4 encephalopathy leads to death. Because ifos- famide-induced encephalopathy research is limited to case reports and small retrospective case series, the prognosis and sequelae according to the toxicity grade, has not been clearly established [10]. Although factors predisposing to ifosfamide-induced encephalopathy have not yet been revealed, rates of neurotoxicity may be increased by pre-existing renal or hepatic failure, low albumin and poor performance status [4,15]. These two cases were considered as grade 4 ifosfamide-in- duced encephalopathy according to the National Cancer Institute Toxicity Grading for Encephalopathy [14] and both resulted in death within 1 month. In case 1, the electroencephalogram (EEG) finding was also re- vealed as Meanwell grade IV [5]. Both patients’clinical courses may have been aggravated by their decreased renal function [10]. Ifosfamide-induced encephalopathy is a clinical diagnosis. The differ- ential diagnoses of ifosfamide-induced encephalopathy include infection, metabolic abnormalities and concomitant drug-induced syndromes. It is supported by normal brain imaging, EEG findings of metabolic en- cephalopathy and the absence of other causes [6]. EEG characteristics have been correlated with the clinical grading of ifosfamide-induced en- cephalopathy [5]. For example, Meanwell grade 3 toxicity has been as- sociated predominantly with delta wave activity, with or without sharp complex waveforms, whereas patients with grade 4 toxicity exhibit con- tinuous delta activity, complex waveforms and triphasic waves. The EEG recording in case 1 showed evidence of grade 4 toxicity (Fig. 1). In patients experiencing acute ifosfamide-induced encephalopathy, the mainstays of management include the prompt cessation of ifosfamide in- fusion and intravenous hydration. Although ifosfamide-induced en- cephalopathy usually reverses completely within 2-3 days after the Fig. 1. Electroencephalogram (EEG) recording in case 1, showing frequent diffuse 1 Hz periodic triphasic waves and rhythmic delta slowing (EEG recording parameters: amplitude, 1 cm=70 μV; interval between two thick vertical lines=1 sec). 262 CANCER RESEARCH AND TREATMENT