Supplementary Material for: Neuron-Specific Enolase as a Biomarker in Ifosfamide-Induced Encephalopathy: A Case Report

Introduction
Ifosfamide, an alkylating agent is used in treatment of various malignancies and may cause encephalopathies. The pathophysiology of this treatment adverse event is well-documented, complex and multifactorial, and involves the production of drug-related metabolites interfering with the normal functionality of neuronal synapses. Risk factors associated with the development of ifosfamide-induced encephalopathy have been identified including concurrent cisplatin administration and female gender. The clinical symptoms vary, ranging from simple confusion to seizure or coma. To date, no biomarkers have been evaluated in ifosfamide-induced encephalopathy. Neuron-specific enolase (NSE) elevation has already been correlated with in toxic or metabolic encephalopathies regardless of the underling etiology.

Case Presentation
We report the case of a 56-year-old woman who received adjuvant chemotherapy for high-grade osteosarcoma including cisplatin, doxorubicin and ifosfamide. The patient experienced ifosfamide-induced encephalopathy the day after completion of the ifosfamide infusion protocol. Treatment with methylene blue was initiated as soon as confusion developed. The patient presented behavioral problems, cognitive impairment, agitation and aphasia, which resolved within few days, with persistent fatigue. NSE levels were assessed after every electroencephalogram (EEG). The kinetics of NSE levels from 20.41 to 7.69 µg/L and EEG toxic pattern improving from grade 2 to normal, were consistent with recovery from clinical encephalopathy in this patient.

Conclusion
Although increased levels of NSE in peripheral blood have been correlated with other etiologies of encephalopathy, its use as a companion biomarker for ifosfamide-induced encephalopathy warrants further investigation.

引言
异环磷酰胺（Ifosfamide）作为一种烷化剂，被用于多种恶性肿瘤的临床治疗，但该药物可能诱导脑病的发生。该治疗相关不良事件的病理生理学机制已被充分阐明，过程复杂且呈多因素性，涉及药物相关代谢产物干扰神经元突触的正常功能。现已明确异环磷酰胺诱导脑病的相关危险因素，包括同时给予顺铂（cisplatin）以及女性性别。其临床症状表现多样，可从轻度意识模糊进展至癫痫发作甚至昏迷。截至目前，尚未有针对异环磷酰胺诱导脑病的生物标志物相关评估研究。神经元特异性烯醇化酶（Neuron-specific enolase, NSE）水平升高已被证实与各类病因导致的中毒性或代谢性脑病相关，无论其潜在致病机制如何。

病例报告
本案例报告一例56岁女性高级别骨肉瘤患者，其接受了包含顺铂、多柔比星（doxorubicin）及异环磷酰胺的辅助化疗方案。该患者在异环磷酰胺输注方案结束次日出现异环磷酰胺诱导的脑病。患者出现意识模糊后，随即启动亚甲蓝治疗。患者表现出行为异常、认知障碍、躁动及失语症状，上述症状在数日内缓解，但仍持续存在疲劳感。每次脑电图（Electroencephalogram, EEG）检查后均对患者的NSE水平进行检测。患者的NSE水平从20.41 μg/L降至7.69 μg/L，脑电图中毒性表现从2级恢复至正常，上述变化与该患者临床脑病的恢复过程相符。

结论
尽管外周血NSE水平升高已被证实与其他病因导致的脑病相关，但将其作为异环磷酰胺诱导脑病的伴随生物标志物仍需开展进一步研究。