长期生酮饮食治疗儿童难治性癫痫的前瞻性多中心研究

Prospective multicenter study on long-term ketogenic diet therapy for intractable childhood epilepsy

目的了解长期生酮饮食（ketogenicdiet，KD）治疗儿童难治性癫痴的疗效和安全性。方法采用前瞻性研究设计，对国内5家医院儿科癫痫中心2004年10月至2011年7月采用经典4：1KD[脂肪：（葡萄糖＋蛋白）质量比为4：1]治疗的299例难治性癫痫患儿，男189例，女110例，根据年龄（〈1岁、-3岁、-6岁、-10岁、〉10岁）、癫痫病因（隐源性、症状性、原发性）和类型（婴儿痉挛症、Lennox—Gastaut综合征、大田原综合征、结节性硬化症、Dravet综合征、全面性癫痫、部分性癫痫）进行分组。KD启动后，家长须记录每日发作情况（包括发作形式、频率和严重程度等）、对KD的耐受性以及并发症，每周测量体重、身高，定期监测血B羟丁酸、血糖、尿酮体。每个月对患儿进行电话随访，第3、6、12个月到医院随访，复查身高、体重、血生化、泌尿系统超声、脑电图和骨骼发育情况等。用SPSS17．0软件统计分析各组的保留率（即继续接受治疗的比率）和发作改善情况。结果KD治疗后3、6、12个月，分别有197例（65．9％）、134例（44．8％）和79例（26．4％）继续接受KD治疗，其中37例（12．4％）、28例（9．4％）和16例（5．4％）发作次数减少50％～90％，75例（25．1％）、50例（16．7％）和45例（15．1％）发作减少〉90％，包括65例（21．7％）、32例（10．7％）和33例（11．O％）无发作。有效率（发作减少〉50％）分别为37．1％、26．1％和20．4％。不到3个月即终止KD治疗的患儿102例（34．1％），其中33例KD治疗时间不足1个月（11．0％）。24个月时，29例继续接受治疗，其中28例发作减少〉90％，包括24例无发作。36个月时，7例保留，发作减少均〉90％，其中5例无发作。KD对不同类型或不同年龄组难治性癫痫的疗效差异无统计学意义。大部分并发症轻微，且可保守治疗缓解，其中，胃肠道功能紊乱（包括呕吐、腹泻、便秘、腹痛等）是最常见的并发症，仅4例患儿出现严重并发症，包括严重代谢紊乱，重症肺炎。结论KD对儿童难治性癫痫有一定的治疗作用，且较为安全。

Objective To evaluate the efficacy and safety of long-term ketogenic diet （KD） on the children with intractable epilepsy. Method This was a prospective, open-label study of intractable epilepsy patients treated with the classic KD with a lipid-to-nonlipid ratio 4：1 between October 2004 and July 2011 at five Chinese epilepsy centers. A total of 299 patients were enrolled. The patients were divided into different groups according to age （including the below-l-year-old group, 1-to-3-year-old group, 3-to-6-year-old group, 6-to-10-year-old group, and over-10-year-old group）, etiology （cryptagenic epilepsy, symptomatic epilepsy, and idiopathic epilepsy ）, and the seizure types （included infantile spasm, Lennox-Gastant syndrome, Ohtahara syndrome, tuberous sclerosis, Dravet syndrome, generalized epilepsy, and partial epilepsy）. Parents were assigned to write seizure diaries which recorded the seizure presentations,tolerability, and complications associated with the KD. Patients＇ weight and height were measured every week. Blood β-hydroxybutyric acid, blood sugar, and urinary ketone bodies were monitored closely. Patients were followed up through telephone calls by the nutritionists every month and regular outpatient visits or hospitalizations were recommended at all time-points which included the third, sixth and twelfth month after initiation. Efficacy was measured through seizure frequency. The variables related to the efficacy were also analyzed. SPSS 17.0 was used for all statistical analysis. Result At 3, 6, and 12 months after initiation, 65.9% ,44. 8%, and 26.4% patients remained on the diet,and 37.4% ,26. 1%, and 20.4% had a 〉 50% reduction in their seizure frequency, including 21.7%, 10. 7%, and 11.0% who became seizure free, respectively. At 24 months after initiation, 29 patients remained on the diet, and 28 patients had a 〉 90% seizure reduction, including five became seizure free. At 36 months after initiation, 7 patients remained on the diet, and all of them had a 〉 90% seizure reduction, including five became seizure free. No significant variables were related to the efficacy. Most complications were mild and reversible by conservative treatment. Gastrointestinal disturbances were the main complications, which included vomiting, diarrhea, constipation, and abdominal cramp. Severe complications occurred in four cases, including severe metabolic disturbances and severe pneumonia. Conclusion The KD is a safe and effective alternative therapy for intractable childhood epilepsy.