学习班-生酮饮食治疗顽固性癫痫.ppt

1、生酮饮食治疗顽固性癫痫,Ketogenic Diet in Refractory Epilepsy,营养科 王觐,癫痫病是神经系统特别是小儿神经系统的常见病。癫痫发作是一种脑细胞生物电活动发生紊乱所产生的症状,癫痫发作表现： 强直性发作 阵挛性发作 失张力发作 失神发作（小发作,多数患者的癫痫发作可以得到很好的控制，当发作控制不理想时会造成大脑的损害、孩子发育倒退，严重影响生活质量,早在上世纪就有人发现饥饿可以有效地控制癫痫发作，随后提出通过改变饮食中营养素的比例来达到与饥饿相同的作用,生酮饮食是一种高比例、适量蛋白质和低碳水化合物的饮食，它将身体的主要代谢能源从利用葡萄糖转变为利用脂肪，通过

2、肝脏代谢产生酮体，从而导致机体的一系列反应。 酮体乙酰乙酸、B-羟丁酸、丙酮 。 酮体是脂肪酸在肝细胞分解氧化时产生的特有中间代谢物,Types,Atkins饮食方案(the modified Atkinsdiet) ：由于在婴幼儿中，摄入不足导致的饥饿常常是致命性的，于是Atkins发明了一种改良的KD。其不限制蛋白质和能量摄人，碳水化合物推荐摄入量在儿童为20 gday，其脂肪与蛋白质加碳水化合物的比例为09：1。在大规模的儿童实验中显示，此种疗法的有效率接近50(有效率指癫痫发作频率缓解程度50,经典KD方案(classic KD)：最早使用也是最经典的一种方案主要由长链甘油三酯(1on

3、g chain triglyceride，LCT)和少量的蛋白质、碳水化合物组成，脂肪与蛋白质加碳水化合物之和的比例为3：1或者4：1,由中链甘油三酯(medium chain triglyeeride，MCT)组成的生酮饮食方案：1971年由Huttenloeher所报道。由于提供相同能量所产生的酮体更多，所以其脂肪与蛋白质和碳水化合物的比例为15：1,生酮饮食疗法的应用： 治疗难治性癫痫、线粒体疾病、葡萄糖转运体1缺乏症和丙酮酸脱氢酶缺乏症等,Some medical researchers and physicians are using ketogenic, carb restrict

4、ed diets to,Drive cancer into remission with new and effective cancer treatments. Improve epilepsy treatment outcomes by reducing, and in some cases, eliminating seizures. Help patients with Alzheimers disease regain memory and thought function. Give diabetics control over their blood glucose with m

5、ore effective diabetes treatment plans. Eliminate gluten allergy symptoms and relieve the symptoms of other allergic conditions associated with autoimmune reactions,The ketogenic diet is well known in the epilepsy treatment field because it is being used with increasing frequency to treat epileptic

6、seizures, especially in children. The diet is extremely effective and more importantly, its non-toxic and well tolerated, although it seems that the hospitals make the diet harder than it has to be. Consider the fact that millions of people put themselves on a low carb ketogenic diet every year and

7、they seem to tolerate it with relish, because they get to eat real, whole fat foods,文献支持（一,A total of 150children were entered into a study of the ketogenic diets efficacy and tolerability. The results were remarkable. Of the original 150patient cohort, 20 of the children(13%) became seizure-free an

8、d an additional 21(14%) had a 90% to 99% decrease in their seizures. In addition, twenty-nine of the children became free of medications, and 28were on only 1medication. Cheryl Hemingway, MB ChB, John M. Freeman, MD, The Ketogenic Diet: A 3- to 6-Year Follow-Up of 150 Children Enrolled Prospectively

9、. Pediatrics Vol. 108 No. 4 October 1, 2001 .pp. 898 -905,14 children with intractable epilepsy and RC complex defects who were treated with the classic ketogenic diet involving a 4:1 lipid to nonlipid ratio (% by weight), but without an initial fast and fluid restriction. Of the 14 patients, half b

10、ecame seizure-free after commencing the diet. One patient with a greater than 90% seizure reduction, and 2 patients had seizure reductions between 50% and 90%. Thats a 50% cure rate, and a seizure reduction rate of 71%. Kang HC, Lee YM, Safe and effective use of the ketogenic diet in children with e

11、pilepsy and mitochondrial respiratory chain complex defects. Epilepsia. 2007 Jan;48(1):82-8,文献支持（二,The ketogenic diet can be given to babies as an epilepsy treatment as well. In this study, during a 4-year period, 23 children with infantile spasms, aged 5 months to 2 years, were started on the ketog

12、enic diet. At 3 months, 38% of the children were greater than 90% improved. At nine months, 53% had greater than 90% improvement, and at 12 months, 46% were more than 90% improved, and the rest were 50% improved. Fifty-seven percent had their medications reduced or discontinued by 12 months and fift

13、y-seven percent had improvement in development, which was correlated with seizure control. Kossoff EH, Pyzik PL, Efficacy of the ketogenic diet for infantile spasms. Pediatrics. 2002 May;109(5):780-3,文献支持（三,通过促皮质素( ACTH) 与生酮饮食( KD) 治疗新发婴儿痉挛症( IS) 的随机对照研究，比较二者的疗效、安全性、耐受性,操德智，胡雁等。促皮质素与生酮饮食治疗新发婴儿痉挛症的随机

14、对照研究。J Appl Clin Pediatr，Vol 26 No 18，Sep 2011,文献支持（四,结论： ACTH 治疗IS 起效较KD 快，近期疗效优于KD 治疗，但其停药后复发率逐渐增高，远期疗效不及KD 治疗，提示KD 可考虑作为IS 的首选治疗方案,These studies suggest that in children, the ketogenic diet results in short to medium term benefits in seizure control, the effects of which are comparable to modern

15、antiepileptic drugs,Levy RG, Cooper PN, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database of Systematic Reviews 2012, Issue 3,提示,KD vs Drugs Epilepsy drugs frequently fail to provide real help, and worse, the drugs cause further harm to the children through toxic si

16、de effects,KD vs Drugs,In contrast, epilepsy drugs frequently fail to provide real help, and worse, the drugs cause further harm to the children through toxic side effects,Cooking,Given the non toxic effectiveness of the ketogenic epilepsy diet, and the harm that drugs can do, Why do physicians and

17、hospitals try drugs first as an epilepsy treatment? why dont they try the ketogenic diet first to treat epilepsy,What makes the ketogenic diet so effective,KD 的作用机制,酮血症是KD抗癫痫作用的主要机制：早期学者们认为，-羟丁酸(-OHB)水平的升高参与了KD的抗癫痫作用。动物实验显示，血浆-OHB水平较低时，发作潜伏期较短，但血浆-OHB水平和发作潜伏期之间无明显正相关，-OHB可能起间接作用。Bough等报道-OHB浓度与控制癫痫发

18、作无相关性。体外研究-OHB和乙酰乙酸对海马一内嗅皮层和海马神经元的作用发现，酮体不能改变这些模型的突触传递，提示KD的抗癫痫作用不是由于酮体直接改变海马突触传递的兴奋性或抑制性. Phelps SJ，Hovinga CA，Rose DF，et o1The ketogenic diet in pediatric epilepsyJ1Nutr Clin Pratiee，1998，13(6)：267282 Harney JP，Madara J，Madara J，et o1Efeets of acute inhibition of fatty acid oxidation on latency to

19、 seizure and concentrations of beta hydroxybutyrate in plasma of rats maintained on calorie restriction andor the ketogenicdiet Epilepsy Res，2002，49(3)：239246 Bough KI，Chen RS，Eagles DAPath analysis shows that increasing ketogenic ratio，but not betahydroxybutyrate，elevates seizure threshold in the r

20、atJJDev Neurosei，1999，21(3-5)：400406 Thio LL， Wong M， Yamada KA Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptictransmissionJ1Neurology， 2000，54(2)：325331,KD 的作用机制 KD抑制红藻氨酸诱发癫痫大鼠的癫痫发作，主要是由于抑制了海马CA1区的兴奋性,Stafstrom CE， Wang C， JensenFE Electr0physi0l0 calobservations i

21、n hippocampal slices from rats treated with the ketogenic diet fJJDev Neurosci，1999，21(35)：393-399,KD 的作用机制 KD引起脑内氨基酸代谢的变化；由于能源物质利用的转变，以葡萄糖为主转化为酮体为主，使脑内氨基酸发生如下变化；天门冬氨酸前体草酰乙酸水平下降，谷氨酸转化为天门冬氨酸减少，而转化为 -氨基丁酸(GABA)增多，后者发挥其效应,Yudkof M， Daikhin Y， Nissim I， et Ketogenic diet，amino acid metabolismand seizure

22、 control fJ1J NeurosciRes，2001，66(5)：931940,KD 的作用机制 KD通过激活阿糖腺苷A1受体，发挥受体调节腺苷激酶的作用，起到抑制癫痫作用,Masino S， Li T， Theofilas，et a1 A ketogenic diet suppresses seizures in mice through adenosine A1 receptors J Clin Invest，201 1，121(7)：26792683,KD 的作用机制 KD通过抑制哺乳动物雷帕霉素的靶点(mammalian target of rapamyein，mTOR)信号传

23、导途径起到对癫痫的抑制作用,Sharon SD，Nicholas RR，Liu LT，et a1The ketogenic diet inhibits the mammalian target of rapamycin(mTOR)pathwayJ 3Epilepsia2011，52(3)：0711,KD 的作用机制 KD抗癫痫的机制可能与线粒体的合成增加、能量代谢、以及多不饱和脂肪酸的作用有关,Bough KJ，Rho JMAnticonvulsant mechanisms of the ketogenicdietJEpilepsia，2007，48(1)：43-58,机制： 可能是多种途径共

24、同作用,研究对象： 以3种（及以上）抗癫痫药物联合治疗失败，或对抗癫痫药物过敏无法控制癫痫发作的难治性癫痫病患者为研究对象,生酮饮食治疗前的评估评估的内容包括：对患儿营养状态的评估(如：身高、体重、BMI、能量摄入水平等)。相应的实验室检查(如：血常规、电解质、血糖、血脂、尿常规等)。根据情况选择相应的特殊检查(如：脑电图、头部影像学检查、腰穿脑脊液检查)。预计在治疗过程中可能出现并发症的风险(如：肾结石、血脂异常、生长发育迟滞、胃食管返流等,启动生酮饮食治疗 患儿住院期间，在开始生酮治疗前，应充分禁食，可以禁食四餐至五餐，但一般不超过36h。如患儿出现面色苍白、出汗、乏力时，应警惕发生低血糖，测微量血糖，当血糖低于22 mmolL时，立即口服纯牛奶或鲜果汁2