生酮饮食在儿童癫(癎)治疗中的应用进展

用含脂肪比例高、蛋白质和碳水化合物比例低的饮食配方,通过脂肪分解代谢产生酮体模拟身体对饥饿的反应治疗癫(癎)等疾病,这种饮食治疗方法称为生酮饮食疗法.目前生酮饮食治疗癫(癎)的确切机制尚不清楚.有关生酮饮食治疗儿童难治性癫(癎)的疗效,系统分析显示无发作的病例达到15.6%(95%CI为10.4%～20.8%),33%(95%CI为24.3%～41.8%)病例获得发作减少50%以上的效果.且该方法不良反应少.因此成为儿童难治性癫(癎)治疗的主要方法之一.本文就生酮饮食的可能机制、高效、适应证及禁忌证等进行介绍.     

生酮饮食在儿童癫治疗中的应用进展

用含脂肪比例高、蛋白质和碳水化合物比例低的饮食配方,通过脂肪分解代谢产生酮体模拟身体对饥饿的反应治疗癫等疾病,这种饮食治疗方法称为生酮饮食疗法。目前生酮饮食治疗癫的确切机制尚不清楚。有关生酮饮食治疗儿童难治性癫的疗效,系统分析显示无发作的病例达到15.6%(95%CI为10.4%～20.8%),33%(95%CI为24.3%～41.8%)病例获得发作减少50%以上的效果。且该方法不良反应少。因此成为儿童难治性癫治疗的主要方法之一。本文就生酮饮食的可能机制、高效、适应证及禁忌证等进行介绍。     

儿童难治性癫(癎)的诊断及治疗方案

目前国内外对儿童难治性癫(癎)的诊断缺乏统一标准.国内建议的诊断标准为癫(癎)患儿经应用正规的抗癫(癎)药物(2种以上)合理治疗6 个月～1 a,发作仍未能减少50%者定为儿童难治性癫(癎).国外文献中,因儿童癫(癎)类型和研究目的 不同,其所制定的诊断标准也各有不同,在诊断标准中均包含4个因素:抗癫(癎)药物无效;惊厥发作的频率;治疗无效的持续时间;惊厥缓解期的持续时间.亦有认为2种选择正确的抗癫(癎)药物治疗无效;惊厥发作平均每月1次,持续≥18个月;在该18个月中,惊厥缓解期的持续时间≤3个月考虑药物难治性癫(癎).目前国内外公认的儿童难治性癫(癎)的治疗方案有3种选择:1.调整抗癫(癎)药物或其他药物,如激素和静脉注射用丙种球蛋白;2.外科治疗,包括治疗性手术(如局灶切除术和大脑半球切除术)和姑息性手术(如胼胝体切除术和迷走神经刺激);3.生酮饮食.     

奥卡西平治疗儿童癫(癎)的临床随访研究

目的 探讨奥卡西平治疗儿童癫(癎)部分性发作及难治性癫(癎)的临床疗效和安全性.方法 2005-2006年上海新华医院小儿神经科收治癫(癎)患者52例,其中新诊断和未经治疗癫(癎)部分性发作患者37例为单药治疗组;15例为既往经2种以上抗癫(癎)药正规治疗,发作仍未控制者为添加治疗组.起始剂量5～10 mg/(kg·d),每日2次口服,每5～7 d,增加5～10 mg/(kg·d),目标剂量20～40 mg/(kg·d).观察期为6个月至2年,进行自身对照开放性研究,观察其疗效、安全性及依从性,分析剂量与不同年龄及疗效的关系.结果 单药治疗组有效率为(控制+显效+有效)89.19%,控制率为67,57%,退出率为2.70%;难治组有效率为46.67%,控制率为13.33%,退出率为26.67%.共5例退出,1例因皮疹退出,4例因发作未能控制而退出.小于4岁患儿的平均剂量较年长儿显著增高(P＜0.05).发作减少50%以上的病例的平均剂量较发作减少50%以下者显著增高(P＜0.05).21.15%的病例发生不良反应,包括困倦、头晕、乏力、皮疹等,无低钠血症发生.结论 奥卡西平治疗儿童部分性癫(癎)疗效显著,对难治性癫(癎)的也有一定的疗效,临床应用依从性良好,不良反应较少,安全性好.     

拉莫三嗪治疗不同类型癫癎患儿10年开放性自身对照研究

目的 评价拉莫:三嗪(LTG)添加及单药治疗小儿不同类型癫癎的疗效及安全性.方法 按1981年及1989年国际抗癫癎联盟的癫癎发作分类,将诊断为各类型癫癎的124例患儿分为非难治性组93例,难治性组31例.使用LTG单药或添加治疗,添加治疗者给药方法为:原抗癫癎药种类和剂量不变,加用LTG逐渐增加至出现发作明显减少或出现明显不良反应如皮疹、肝肾功能损害等时停止,根据治疗前3个月基线月均发作频率,将每例最后3个月的月均发作频率与基线进行比较,并观察其不良反应.结果 总有效率72.6%,控制率51.6%,非难治性组总有效率81.0%,控制率61.3%,较难治组(48.4%、22.6%)明显提高.LTG与丙戊酸钠(VPA)合用组有效率78.4%.控制率54.5%,与未合用VPA组(61.0%,44.0%)比较无显著性差异(P＞0.05).病程观察期＜5 a与＞5 a应用LTG的疗效有显著性差异(P＜0.05).LTG与VPA合用时疗效较好,且可减少LTG剂量,不良反应主要有嗜睡、头晕等.结论 LTG治疗小儿各类型癫癎疗效稳定,耐药性、不良反应少,是适合于长期应用的一种新璎抗癫癎药.     

生酮饮食添加治疗儿童难治性癫癎的前瞻性研究

目的 探讨生酮饮食（ketogenic diet,KD）添加治疗儿童难治性癫癎的临床疗效、脑电图变化及对认知功能的影响。方法 研究对象为2012年8月至2013年8月接受KD添加治疗的20例难治性癫癎患儿。KD治疗方案为启动时禁食,脂肪和蛋白质、碳水化合物比例逐渐增高至4：1。疗效评估方法以KD添加治疗前癫癎发作频率为基线,通过家长的癫癎日记,记录发作的频率、类型及程度的变化,并于添加KD前、添加KD后3、6、9个月分别行24 h视频脑电图检查、Gesell发育量表评定。结果 20例患儿中,临床控制无发作6人,完全控制率为30%;有效13人,总有效率为65%。脑电图改善8人,总有效率为40%;Gesell发育量表评定6人提高一个等级,改善率为30%,改善能区主要在大运动及适应性能区。KD治疗不良反应轻微。结论 KD治疗儿童难治性癫癎安全有效;KD治疗后脑电图改变与临床疗效有一定相关性,且对认知功能有一定改善。     

生酮饮食治疗癫(癎)启动期微量血糖动态监测

目的 观察适合中国人饮食习惯的生酮饮食方案治疗小儿药物难治性癫(癎)启动期血糖的动态变化.方法 2004年10月至2006年12月深圳儿童医院对难治性癫(癎)住院患儿启动生酮饮食治疗,用毛细血管微量血法动态监测血糖变化.禁食48h或禁食已达到酮症状态后开始全量生酮饮食:脂肪与碳水化合物加上蛋白质的质量比为4:1.使用适合中国人饮食习惯的配餐软件辅助配餐.对文献报道的有关并发症进行监测.结果 禁食开始后(26.7±16.4)h达到酮症状态.96h内低血糖阳性例次检出率3.7%(16/427).毛细血管微量血糖法检测低血糖发生率30.0%(9/30),症状性低血糖发生率10.0%(3/30).对低血糖患者给予牛奶10～20mL口服,患者很快恢复,没有出现严重低血糖症.拒食、呕吐可能加重低血糖.结论 用适合中国人饮食习惯的生酮饮食治疗小儿药物难治性癫(癎)启动期,特别是禁食期间血糖波动,需要密切监测,及时处理低血糖.生酮饮食启动期是安全的.     

激光氧液加东莨菪碱辅助治疗儿童难治性癫(癎)的疗效

目的 观察激光氧液加东莨菪碱(LOFS)辅助治疗儿童难治性癫(癎)的临床效果.方法 选择1～14岁难治性癫(癎)患儿68例,在原有抗癫(癎)治疗基础上,采用DJF-IA型多功能激光血液治疗仪,以50g·L-1葡萄糖5～10 mL·kg-1作载体,置于血疗仪中,接受He-Ne激光照射15 min,并充氧,加用东莨菪碱0.01～0.03 mg·kg-1,静脉滴注1次·d-1,每月10 d,连续3个疗程.结果 LOFS辅助治疗前3个月内各类型癫(癎)发作总频次为每月34 792(659.00±31.24)次;LOFS治疗3个月过程中发作总频次为每月965(14.00±5.36)次,较原基线平均下降89.99%(t=7.36,P＜0.01),总有效率为95.59%.LOFS治疗前全部患儿脑电图中的(癎)性放电率为100%,治疗后脑电图(癎)性放电率平均为68.5%,其中7例脑电图完全恢复正常(10.29%),此7例中6例抽搐次数明显减少,1例抽搐次数未减少.脑电图在治疗前后无明显变化的52例中,发作频次减少≥50%者50例(69.15%),脑电图的变化与临床症状改善程度不完全一致.结论 LOFS可能成为难治性癫(癎)的一种新的辅助治疗手段.     

拉莫三嗪添加治疗难治性癫癎的疗效及安全性

目的探讨拉莫三嗪(LTG)添加治疗难治性癫癎的疗效和安全性。方法难治性癫癎68例.以开始治疗前3个月患儿平均每月发作次数为基线,与LTG治疗3个月后平均每月发作次数比较。按常规计算完全控制率和有效率。并进行临床观察。结果完全控制率27.9%;有效率544%。19例次出现不良反应,但大部分症状轻微,可自行消失。结论LTG添加治疗儿童难治性癫癎疗效显著,安全性好。     

左乙拉西坦单药治疗小儿癫癎的疗效和安全性随访研究

目的：评价左乙拉西坦(LEV)单药治疗小儿癫癎的疗效和安全性。方法：对该院2007年3月至2008年3月LEV单药治疗的32例癫癎患儿进行开放性自身对照随访研究,起始量每日10 mg/kg,每1周增加上述剂量1次,3~4周增加至维持剂量每日20～60 mg/kg,平均剂量为每日35 mg/kg。结果：LEV 单药治疗32例,失访1例,其余随访均在3个月以上。 80.6%（25/31）患儿发作减少≥50%,70.9%（22/31）患儿无发作,16.1%（5/31）患儿因发作控制不满意或者加重而停药。不良反应包括情绪异常19.4%（6/31）,乏力6.5%（2/31）,嗜睡6.5%（2/31）,皮疹3.2%（1/31）。上述不良反应均为一过性,在1～4 周内自然消失或者减量后消失,未导致停药,未发现过敏以及血液、肝、肾功能异常等严重不良反应。结论：LEV用于癫癎患儿（包括<4岁的婴幼儿）的部分性发作及全身性发作的单药治疗,疗效肯定、安全性好,是一个很有希望的用于儿童单药治疗的广谱抗癫癎药。     

The ketogenic diet in refractory epilepsy: the experience of Children's Hospital of Pittsburgh

The ketogenic diet appears to be effective in reducing seizure frequency in patients with epilepsy refractory to antiepileptic drug therapy. Reported seizure frequencies before and after the diet was initiated were obtained for 48 patients started on the ketogenic diet between December 1994 and January 1998 at Children's Hospital of Pittsburgh. The majority of patients (71%) were able to achieve > or = 50% reduction in seizure activity. Of these, more than half (53%) had > 90% reduction in seizures after 45 days of diet therapy. Complications included gastrointestinal complaints and infrequent lipid abnormalities. The ketogenic diet appears to be an effective method of treatment for children with epilepsy refractory to drug therapy.     

The ketogenic diet in German-speaking countries: update 2003

BACKGROUND: The ketogenic diet has been used for decades to treat intractable childhood epilepsies. It is also the treatment of choice for GLUT1 deficiency syndrome and pyruvate-dehydrogenase-complex-deficiency. Recent studies have once again confirmed the efficiacy of the diet, but the diet is hardly known in Europe and has never been quite accepted as an effective treatment of childhood epilepsy. PATIENTS: We report retrospective data on 146 children treated with the ketogenic diet in Austria, Switzerland, and Germany. METHOD: In 2000 and 2002, standardized questionaires were sent to 13 neuropediatric departments to evaluate indications, effects and side effects. RESULTS: In children with refractory epilepsy (n = 111), 8 % became seizure-free on the diet. Seizure reduction of > 90 % was achieved in additional 9 % of patients, a seizure reduction of 50-90 % in additional 14 % of patients. There was a great variability between epilepsy departments. All patients with GLUT1 deficiency syndrome (n = 18) and pyruvate-dehydrogenase-complex-deficiency (n = 15) showed clinical improvement. In GLUT1 deficiency syndrome, complete seizure control was achieved in 94 % of patients. Compliance was good in 82 % of all patients regardless of the indication for the diet. CONCLUSION: In contrast to the general restraint towards the ketogenic diet in Europe, our data supports its effectiveness as the treatment of choice for GLUT1-deficiency syndrome und pyruvate-dehydrogenase-complex-deficiency. In children with refractory epilepsy, the ketogenic diet matched the effect of most anticonvulsants and was well tolerated. These data and two workshops resulted in recommendations for the use of the ketogenic diet in children as a basis for a general diagnostic and therapeutic standards to compare and improve the use of the ketogenic diet in Europe.     

Ketogene Di?t bei refrakt?rer Epilepsie im Kindesalter

About 10% of epilepsies in childhood are refractory to anticonvulsants. Here the ketogenic diet has been re-established as an effective treatment option worldwide. Restriction of carbohydrates and a high lipid diet can result in seizure control similar to anticonvulsants. A pediatric/dietary team, supplements, and close support are required to establish and maintain a ketogenic diet and manage potential adverse effects. Different ketogenic diets are available and follow established standards to meet the individual needs of the patient. If ineffective, the diet can easily be terminated. If effective, it can be maintained for 2?years and seizure control may persist even when the diet is discontinued. Metabolic indications for the ketogenic diet are GLUT1 deficiency syndrome and pyruvate dehydrogenase deficiency ?C here the diet is the treatment of choice as ketones serve as an alternative fuel to the brain restoring brain energy metabolism. For refractory childhood epilepsy the ketogenic diet should be considered in line with vagus nerve stimulation and epilepsy surgery.     

Ketogenic regime as anti-epileptic treatment: its use in 29 epileptic children]

INTRODUCTION: The ketogenic diet is a treatment option for patient with intractable or refractory epilepsy. It is a high-fat, low protein, low carbohydrate diet developed in 1920s. Recent research publications and media interest have renewed debate on the merits of ketogenic diet. POPULATION: We report our experience with 29 children suffering from refractory epilepsy, treated with the ketogenic diet. No surgical option was available. Modalities are explained. RESULTS: The ketogenic diet improved seizure control in 12/29 cases. It appeared effective in infants with infantile spasms. Refractory-status epilepticus responded to the ketogenic diet (3/6 cases). Migrating partial seizures in infancy were always refractory to the diet. Compliance with the diet was good. Adverse effects must be compared with the toxicity of antiepileptic drugs. One child had hypokaliemia with cardiac complication. CONCLUSION: The ketogenic diet should be continued during one or 2 years when it is effective. It should be considered as an alternative therapy for children with refractory epilepsy.     

Non-Pharmacologic Management of Epilepsy

Non pharmacological treatment, in addition to pharmacological treatment is indicated in patients with refractory/pharmacoresistant epilepsy and includes ketogenic diet, deep brain stimulator, vagal nerve stimulator, transcranial magnetic stimulation and epilepsy surgery. Ketogenic diet has been recommended since 1921 and has been proved to be a safe and effective treatment for intractable epilepsy. Deep brain stimulator, has been used in the treatment of movement disorders for many years and recently been tried in the treatment of pharmacoresistant epilepsy. Vagus nerve stimulator is increasingly being used as an effective seizure aborting technique in patients not responding to anticonvulsants. Transcranial magnetic stimulation is a noninvasive brain stimulation technique which is being increasingly researched for use in patients with medication-refractory seizures who are not suitable candidates for surgery. Evolution of epilepsy surgery including Vagal nerve stimulator and Deep brain stimulator, as a successful treatment modality for intractable epilepsy has been influenced over the last decade by substantial advancement in imaging and operative/device related technology. The current article reviews the indications, mechanism of action, technological aspects and efficacy of the aforementioned modalities in the treatment of intractable/pharmacoresistant epilepsy in pediatric age group.     

Indikation und Anwendung der ketogenen Diät im Kindesalter1. Workshop ketogene Diät am 15. Dezember 2000 in Essen

The ketogenic diet, a high fat, low carbohydrate diet, is the treatment of choice for pyruvate-dehydrogenase-deficiency and GLUT1 deficiency syndrome, and effective in intractable childhood epilepsy. In Germany the diet is hardly used, protocols are not standardized, and German literature is non-existent. 12/2000 physicians and dietitians using the ketogenic diet in Germany met. In 52 patients a good response was seen in pyruvate-dehydrogenase-deficiency (n = 7) and GLUT1 deficiency syndrome (n = 9). In intractable childhood epilepsy (n = 36) the effect of the ketogenic diet was rated as good in 3 patients (8%), moderate in 14 patients (39%), and poor in 19 patients (53%). Compliance was good and few side effects were observed. Standards for the introduction and maintenance of the ketogenic diet were developed and protocols coordinated to ensure quality control and a prospective evaluation of the diet.     

Effektivität der ketogenen Diät bei therapierefraktären Epilepsien

Background.

While in the Anglo-American countries the ketogenic diet (KD) has shown to be efficient in the treatment of refractory epilepsy, an attempt of evaluation in Germany (Workshop 2000 in Essen) showed an unfavorable result (0% seizure-free, seizure reduction >50% in only 16%).

Objective.

As the evaluation in Germany (Workshop 2000 in Essen) did not include the results of our patients, we present the retrospective evaluation of the efficacy of the KD in our patients with refractory epilepsy.

Patients and Methods.

We report 24 patients with refractory epilepsy who have been treated with the KD between February 1997 and January 2002. When the KD was started median (range) of age was 6.0 years (0.8–13.2), number of antiepileptic drugs used previously was 7 (3–13), time since onset of epilepsy 53 months (5–159) and seizure frequency 140/week (250 myoclonic seizures/day up to 1 status epilepticus/month). 13 patients had symptomatic, 8 patients cryptogenic and 3 patients idiopathic epilepsy.

Results.

In 2 patients the KD was stopped during initiation due to side effects (vomiting, sleepiness). Reduction of seizures >50% was achieved in 59% of the patients, 2/22 (9%) have become seizure-free for 22 months respectively 3.8 years. Seizure reduction >90% was achieved in further 5/22 patients (23%) and seizure reduction between 50–90% in further 6/22 patients (27%). At the time of evaluation the responders with seizure reduction >50% have been on the KD for 116 weeks (13–221). There was no significant difference between responders and nonresponders regarding the number of antiepileptic drugs used before the KD, the age and time since onset of epilepsy when the KD was started nor the types of seizures.

Conclusion.

The Ketogenic diet is efficient in reducing seizure frequency in children with refractory epilepsy.     

Prospective study of growth and bone mass in Swedish children treated with the modified Atkins diet

PurposeThe modified Atkins diet (MAD) is a less restrictive treatment option than the ketogenic diet (KD) for intractable epilepsy and some metabolic conditions. Prolonged KD treatment may decrease bone mineralization and affect linear growth; however, long-term studies of MAD treatment are lacking. This study was designed to assess growth, body composition, and bone mass in children on MAD treatment for 24 months.MethodsThirty-eight patients, mean age (SD) 6.1 years (4.8 years), 21 girls, with intractable epilepsy (n = 22), glucose transporter type 1 deficiency syndrome (n = 7), or pyruvate dehydrogenase complex deficiency (n = 9) were included. Body weight, height, body mass index (BMI), bone mass, and laboratory tests (calcium, phosphorus, magnesium, alkaline phosphatase, cholesterol, 25-hydroxyvitamin D, insulin-like growth factor-I and insulin-like growth factor binding protein 3) were assessed at baseline and after 24 months of MAD treatment.ResultsApproximately 50% of the patients responded with more than 50% seizure reduction. Weight and height standard deviation score (SDS) were stable over 24 months, whereas median (minimum – maximum) BMI SDS increased from 0.2 (−3.3 to 4.5) to 0.7 (−0.9 to 2.6), p < 0.005. No effects were observed for bone mass (total body, lumbar spine and hip) or fat mass.ConclusionsThe MAD was efficient in reducing seizures, and no negative effect was observed on longitudinal growth or bone mass after MAD treatment for 24 months.     

The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children

OBJECTIVE: The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet developed in the 1920s for the treatment of children with difficult to control seizures. Despite advances in both the pharmacotherapy and the surgery of epilepsy, many children continue to have difficult-to-control seizures. This prospective study sought to determine the ketogenic diet's effectiveness and tolerability in children refractory to today's medications. METHODS: One hundred fifty consecutive children, ages 1 to 16 years, virtually all of whom continued to have more than two seizures per week despite adequate therapy with at least two anticonvulsant medications, were prospectively enrolled in this study, treated with the ketogenic diet, and followed for a minimum of 1 year. Seizure frequency was tabulated from patients' daily seizure calendars and seizure reduction calculated as percentage of baseline frequency. Adverse events and reasons for diet discontinuation were recorded. RESULTS: The children (mean age, 5.3 years), averaged 410 seizures per month before the diet, despite an exposure to a mean of 6.2 antiepileptic medications. Three months after diet initiation, 83% of those starting remained on the diet and 34% had >90% decrease in seizures. At 6 months, 71% still remained on the diet and 32% had a >90% decrease in seizures. At 1 year, 55% remained on the diet and 27% had a >90% decrease in seizure frequency. Most of those discontinuing the diet did so because it was either insufficiently effective or too restrictive. Seven percent stopped because of intercurrent illness. CONCLUSIONS: The ketogenic diet should be considered as alternative therapy for children with difficult-to-control seizures. It is more effective than many of the new anticonvulsant medications and is well tolerated by children and families when it is effective.     

Behavioural and cognitive effects during vagus nerve stimulation in children with intractable epilepsy – A randomized controlled trial

Background/AimsIn addition to effects on seizure frequency in intractable epilepsy, multiple studies report benefits of vagus nerve stimulation (VNS) on behavioural outcomes and quality of life. The present study aims to investigate the effects of VNS on cognition, mood in general, depression, epilepsy-related restrictions and psychosocial adjustment in children with intractable epilepsy, as well as the relation between these effects and seizure reduction.MethodsWe conducted a randomized, active-controlled, double-blinded, add-on study in 41 children (age 4–18) with medically refractory epilepsy. We performed cognitive and behavioural testing at baseline (12 weeks), at the end of the blinded phase (20 weeks) in children receiving either high-output or low-output (active control) stimulation, and at the end of the open label phase (19 weeks) with all children receiving high-output stimulation. Seizure frequency was recorded using seizure diaries.ResultsVNS did not have a negative effect on cognition nor on psychosocial adjustment. At the end of the follow-up phase we noted an improvement of mood in general and the depression subscale for the entire group, unrelated to a reduction of seizure frequency. At the end of the blinded phase a ≥50% reduction of seizure frequency occurred in 16% of the high-stimulation group and 21% of the low-stimulation group. At the end of the open-label follow-up phase, 26% of the children experienced a seizure frequency reduction of 50% or more (responders).ConclusionsVNS has additional beneficial effects in children with intractable epilepsy. As opposed to anti-epileptic drugs, there are no negative effects on cognition. Moreover, we observed an improvement of mood in general and depressed feelings in particular, irrespective of a reduction in seizure frequency. These beneficial effects should be taken into account when deciding whether to initiate or continue VNS treatment in these children.