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.     

生酮饮食治疗难治性癫(癇)的初步观察

目的观察生酮饮食治疗小儿难治性癫癎的疗效及其安全性。方法选择15例难治性癫癎患儿用合适中国人膳食习惯的生酮饮食方案进行治疗。随访其依从性、临床发作频率及不良反应。结果12例（80%）坚持治疗1个月,其中10例（87.5%）癫癎发作减少〉50%;10例（66.6%）坚持治疗3个月,其中8例（80%）癫癎发作减少〉50%;5例（33.3%）坚持治疗6个月以上,其中5例（100%）癫癎发作减少均〉50%,4例（80%）癫癎发作减少〉90%,3例（60%）癫癎发作完全控制。1例已随访2年以上,发作减少〉90%。10例出现轻重不一的不良反应（恶心、呕吐、腹泻、便秘、低血糖、高血脂、肝功能受损）,经对症治疗后均可缓解。结论适合中国人膳食习惯的生酮饮食方案治疗小儿难治性癫癎有效而安全。其疗效与发作类型无明显关系。     

Seizures decrease rapidly after fasting: preliminary studies of the ketogenic diet.

OBJECTIVES: To evaluate the change in atonic or myoclonic seizures associated with the Lénnox-Gastaut syndrome during the initiation of the ketogenic diet, and to describe the development of a blinded crossover study of the efficacy of the ketogenic diet. DESIGN: A before-after trial. SETTING: The Johns Hopkins Hospital, Baltimore, Md. PATIENTS: Change in clinical seizure frequency was examined in 17 consecutively treated patients with atonic or myoclonic seizures. In a few patients, a 24-hour ambulatory electroencephalogram was obtained before and after diet initiation. We demonstrated the ability to manipulate the ketosis induced by fasting with the addition of glucose (dextrose) in 1 patient. INTERVENTIONS: Children fasted for 36 hours, and the diet was gradually introduced over 3 days. Parents were instructed to keep a baseline seizure frequency calendar for the month before the initiation of the diet. These calendars continued to be maintained as the diet was initiated. MAIN OUTCOME MEASURE: Seizure decrease from baseline. RESULTS: The atonic or myoclonic seizures decreased in these children by more than 50% immediately. Using a 24-hour ambulatory electroencephalogram, we documented that the seizures reported by a parent represent only a fraction of the electroclinical events; the technique could be used to measure the profound decrease in electrically documented seizures. Ketosis was eliminated with glucose, 60 g/d. CONCLUSIONS: It is feasible to evaluate the ketogenic diet's efficacy in atonic or myoclonic seizures in a blinded, crossover study. The diet can be manipulated on a short-term basis in a blinded manner, and ketosis can be achieved or eliminated.     

Levetiracetam in children and adolescents with epilepsy and hemiplegic cerebral palsy

Aim: To monitor the effect of adding levetiracetam in paediatric patients with hemiplegic cerebral palsy and uncontrolled epilepsy. Methods: A case series of eight patients with hemiplegic cerebral palsy whose focal seizures were not adequately controlled by their current anticonvulsants were monitored after levetiracetam was added to their medications. If there was a 50% reduction in seizure frequency, then the other anticonvulsants were discontinued. Prolonged follow‐up occurred for a minimum of 2 years. Results: There were seven males and one female whose ages ranged from 4 years to 17 years. All had focal onset seizures, while seven also had secondarily generalised tonic clonic seizures. Levetiracetam resulted in at least a 50% reduction in seizure frequency in seven, with no change in one. Three were able to wean successfully to monotherapy and remained seizure free for over 2 years. They had a prior history of infrequent seizures, one to six per year. Those who continued to require multiple anticonvulsants had a prior history of more frequent seizures, 6–50/year. Levetiracetam was well tolerated, and none ceased this because of side effects. Conclusion: Levetiracetam is likely to be an effective anticonvulsant in children and adolescents with hemiplegic cerebral palsy and infrequent but persistent focal seizures.     

The ketogenic diet: one decade later

The ketogenic diet, a high fat, adequate protein, low carbohydrate diet, has, during the past decade, had a resurgence of interest for the treatment of difficult-to-control seizures in children. This review traces its history, reviews its uses and side effects, and discusses possible alternatives and the diet's possible mechanisms of action. Finally, this review looks toward possible future uses of the ketogenic diet for conditions other than epilepsy.     

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.     

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.     

Epilepsy and the ketogenic diet: assessment of ketosis in children using breath acetone

High-fat ketogenic diets increase ketones (acetoacetate, beta-hydroxybutyrate, and acetone) and are used to treat refractory seizures. Although ketosis is an integral aspect of these therapeutic regimens, the direct importance of ketosis to seizure control needs further investigation. An examination of this relationship requires a reliable, minimally invasive measure of ketosis that can be performed frequently. In the present study, we examined the use of breath acetone as a measure of ketosis in children with refractory seizures on a classic ketogenic diet. Results were compared with breath acetone levels in epilepsy and healthy controls. Children on the ketogenic diet had significantly higher fasting breath acetone compared with epilepsy or healthy controls (2530 +/- 600 nmol/L versus 19 +/- 9 nmol/L and 21 +/- 4 nmol/L, respectively; p < 0.05). One hour after consumption of a ketogenic breakfast meal, breath acetone increased significantly in epilepsy and healthy controls (p < 0.05), but not in children on a ketogenic diet. Children who were on the ketogenic diet for longer periods of time had a significantly lower fasting breath acetone (R(2) = 0.55, p = 0.014). In one child on the ketogenic diet, breath acetone was determined hourly over a 9-h period, both by gas chromatography and by a prototype hand-held breath acetone analyzer. Preliminary results using this hand-held breath acetone analyzer are encouraging. Breath acetone may be a useful tool in examining the relationship between ketosis and seizure control and enhancing our understanding of the mechanism of the ketogenic diet.     

The medium chain triglyceride diet and intractable epilepsy.

Fifty children with drug resistant epilepsy were treated with the Medium Chain Triglyceride (MCT) Emulsion diet. Eight achieved complete control of seizures (four without anticonvulsant drugs), and with the addition of anticonvulsants four had seizures reduced in frequency by 90% and 10 by 50-90%. The best results were obtained with astatic myoclonic and absence seizures, but control of seizures was improved in four children with tonic-clonic and three with complex partial seizures. Food given at the same time as MCT helped to reduce side effects, and an extra dose of MCT before bedtime improved control of nocturnal seizures.     

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.     

Ketogenic diet for the treatment of catastrophic epileptic encephalopathies in childhood

The ketogenic diet for the treatment of refractory epileptic encephalopathies has been suggested as an early treatment option in very young children. The aim of the present study was to assess the efficacy and tolerability of the ketogenic diet in children younger than 5 years, all affected by different types of catastrophic childhood encephalopathies. The study group is composed of 38 children (22 males and 16 females), aged between 3 months and 5 years, affected by symptomatic partial epilepsy (6) and cryptogenic–symptomatic epileptic encephalopathies (32). Psychomotor delay–mental retardation was present in all of the patients: mild to moderate (9), severe (7), and profound (22). Cerebral palsy was present in 74% of the cases. Children were started on a 4:1 ketogenic diet as ketocal^® formula alone or supporting about the 80% of the daily caloric amount. Children poorly complying with ketocal^® milk were shifted to a classic 4:1 ketogenic diet. The average time (months ± S.D.) on the diet was 10.3 ± 7.4. All the children initiating the diet remained on it at 1 month and 35 of them (92%) at 3 months, 28 (73.7%) remained on it at 6 months, and 20 (52.7%) at 1 year. At 12-month follow-up, 11 children (28.9%) had a greater than 50% reduction of seizures and the other 9 (23.7%) were seizure-free. Adverse side effects were recorded in 25 of 38 patients (65.8%), including drowsiness, constipation, weight loss, vomiting, gastroesophageal reflux, fever, and hyperlipidemia. This report confirms that severe epileptic encephalopathies are much suitable for the ketogenic diet.     

228例儿童癫痫停药后复发的相关因素分析

目的：　通过对临床已获控制并停药随访的癫痫患儿复发情况的分析,总结并讨论与复发有关的因素。方法：　回顾性分析228例临床已获控制并停药随访的癫痫患儿的临床资料。结果：　 228例患儿中51例复发(22.4%),其中92.2%于停药后5年内复发。与复发相关的因素有:起病年龄、伴有神经功能障碍、治疗前发作频率、治疗的早晚、控制期的长短及癫痫的类型(P<0.05)。与复发无关的因素有:达控时间的长短、停药年龄、性别及癫痫家族史(P>0.05)。结论：　对伴有复发危险因素的癫痫患儿应适当延长治疗和随访时间。不伴有以上相关因素的癫痫患儿,在经过正规的治疗和停药以后,可以取得比较满意的效果     

A pilot study of add-on oral triheptanoin treatment for children with medically refractory epilepsy

Aim

Despite antiepileptic medication and dietary treatment options available about 45% of children with epilepsy still suffer from uncontrolled seizures. Triheptanoin is an anaplerotic treatment designed to improve energy generation via the Krebs cycle.

Efficacy and prognosis of a short course of prednisolone therapy for pediatric epilepsy

PURPOSE: To evaluate the efficacy and safety of adjunctive prednisolone therapy in children with cryptogenic epileptic encephalopathy, other than infantile spasms, and to determine its prognosis. METHODS: Prednisolone, 2mg/kg per day for 6 weeks, tapered for a further 2 weeks, was given in combination with previously prescribed antiepileptic drugs. A retrospective assessment of 41 children thus treated included measurements of seizure frequency, electroencephalographic findings, global assessments of cognitive function, and adverse drug events. Long-term patient prognoses over a mean follow-up period of 3 years and 5 months (range, 14-90 months) were also examined. RESULTS: Of 41 patients, 32 had Lennox-Gastaut syndrome, 4 had Doose syndrome, 1 had Otahara syndrome, 2 had Landau-Kleffner syndrome, and 2 had other unspecified generalized epilepsies. After prednisolone therapy, 73% (30/41) of patients showed a reduction in seizure frequency of >50%, and 59% (24/41) became seizure free. However, only seven patients (four with Lennox-Gastaut syndrome, two with Doose syndrome, and one with unspecified generalized epilepsy) who became seizure free remained free of seizures at the time of the final follow-up. Electroencephalographic findings and global assessments of cognitive function correlated well with seizure outcomes. No significant demographic factors influenced the efficacy of prednisolone or patient prognoses after prednisolone tapering. Most adverse events were transient, or were tolerated well with conservative management, with maintenance of the medication. CONCLUSION: Prednisolone therapy may be a safe and effective adjunct in patients with cryptogenic epileptic encephalopathies, but the high relapse rate is of concern.     

Improvement of Modem Treatment and Outcome in Childhood Epilepsy in Asia

Epilepsy and epileptic syndromes are one of the major pediatric neurological diseases in Taiwan, R.O.C. In 1984 we investigated 38 elementary schools in Taichung city, in the middle-west part of Taiwan. Among 57,944 school-aged children, 388 had suffered from at least two episodes of afebrile seizures occurring separately over a two-week period. The period prevalence rate was 0.67%. In our clinic, once seizures are diagnosed, the seizure types are then classified as well as possible, in order to develop a rational approach to treatment. We commonly use carbamazepine for partial seizures and some generalized seizures, low dose ACTH (10 I.U.) for infantile spasms, valproic acid for absence seizures and myoclonic seizures, clonazepam for atonic-akinetic and myoclonic seizures, and phenobar-bital for young children with generalized seizures. In the last three years, we have used a ketogenic diet for akinetic-atonic seizures and Lennox-Gastaut syndrome; we have also used temporal lokctomy for complex partial seizures since 1981. Owing to the marked increase in the medical understanding of epileptic seizures and syndromes, and models of treatment, there is no question that children with seizure disorders are better off today than they were ten years ago.     

The effects of the ketogenic diet in refractory partial seizures with reference to tuberous sclerosis.

PURPOSE: Tuberous sclerosis complex (OMIM 191100) is a multiorgan disease commonly associated with epilepsy refractory to anticonvulsants. Individual reports indicate that seizures in children with tuberous sclerosis might benefit from a ketogenic diet. We studied the effects of the diet introduced at 3.5 years of age in three boys with tuberous sclerosis and refractory partial seizures. METHODS: On admission a classical LCT ketogenic diet was initiated and patients were followed for 12 months. Antiepileptic drugs were maintained unless adverse effects required reduction. RESULTS: Two patients became seizure-free within 2 months on the diet. In the third patient drop attacks decreased significantly. On follow-up the diet was well accepted and without adverse effects. CONCLUSION: The ketogenic diet should be considered as a treatment option for children with tuberous sclerosis and partial seizures refractory to anticonvulsants. Our data support the need for further studies in larger cohorts to confirm the effectiveness of the ketogenic diet in this entity.     

Traditional and non-traditional treatments for autism spectrum disorder with seizures: an on-line survey

Background

Despite the high prevalence of seizure, epilepsy and abnormal electroencephalograms in individuals with autism spectrum disorder (ASD), there is little information regarding the relative effectiveness of treatments for seizures in the ASD population. In order to determine the effectiveness of traditional and non-traditional treatments for improving seizures and influencing other clinical factor relevant to ASD, we developed a comprehensive on-line seizure survey.

Methods

Announcements (by email and websites) by ASD support groups asked parents of children with ASD to complete the on-line surveys. Survey responders choose one of two surveys to complete: a survey about treatments for individuals with ASD and clinical or subclinical seizures or abnormal electroencephalograms, or a control survey for individuals with ASD without clinical or subclinical seizures or abnormal electroencephalograms. Survey responders rated the perceived effect of traditional antiepileptic drug (AED), non-AED seizure treatments and non-traditional ASD treatments on seizures and other clinical factors (sleep, communication, behavior, attention and mood), and listed up to three treatment side effects.

Results

Responses were obtained concerning 733 children with seizures and 290 controls. In general, AEDs were perceived to improve seizures but worsened other clinical factors for children with clinical seizure. Valproic acid, lamotrigine, levetiracetam and ethosuximide were perceived to improve seizures the most and worsen other clinical factors the least out of all AEDs in children with clinical seizures. Traditional non-AED seizure and non-traditional treatments, as a group, were perceived to improve other clinical factors and seizures but the perceived improvement in seizures was significantly less than that reported for AEDs. Certain traditional non-AED treatments, particularly the ketogenic diet, were perceived to improve both seizures and other clinical factors. For ASD individuals with reported subclinical seizures, other clinical factors were reported to be worsened by AEDs and improved by non-AED traditional seizure and non-traditional treatments. The rate of side effects was reportedly higher for AEDs compared to traditional non-AED treatments.

Conclusion

Although this survey-based method only provides information regarding parental perceptions of effectiveness, this information may be helpful for selecting seizure treatments in individuals with ASD.     

Add-on levetiracetam in children and adolescents with refractory epilepsy: Results of an open-label multi-centre study

PURPOSE: To study the efficacy and tolerability of add-on levetiracetam in children and adolescents with refractory epilepsy. METHODS: In this prospective multi-centre, open-label, add-on study, 33 children aged 4-16 years (median 8.5 years) with epilepsy refractory to at least two antiepileptic drugs were treated with levetiracetam in addition to their present treatment regimen with a follow-up of 26 weeks. The starting dose of 10 mg/kg/day was increased with 2-week steps of 10 mg/kg/day, if necessary, up to a maximum dose of 60 mg/kg/day. RESULTS: Retention rate was 69.7% after 26 weeks on a median levetiracetam dosage of 22 mg/kg/day. Four children dropped-out because levetiracetam was ineffective, four because seizure frequency increased and/or seizures became more severe, and two because they developed aggressive behaviour. Compared to their baseline seizure frequency, 13 children (39.4%) had a >50% seizure reduction 12 weeks after initiation of levetiracetam, and 17 children (51.5%) at 26 weeks. At 26 weeks, nine children (27.3%) had been seizure-free for at least the last 4 weeks, terminal remission ranged from 0 to 187 days (mean 46 days). Levetiracetam was effective in both partial and primary generalized seizures, but had most effect in partial seizures. Most reported side effects were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive behaviour (27.3%). Severity of most side effects was mild. Five children had a serious adverse event, which all concerned hospital admissions that were not related to levetiracetam use. CONCLUSION: Levetiracetam proved to be an effective and well-tolerated add-on treatment in this group of children with refractory epilepsy.     

Efficacy of Pregabalin in Childhood Refractory Partial Seizure

Objective: About one third of partial seizures are refractory to treatment. Several anticonvulsant drugs have entered the market in recent decades but concerns about intolerance, drug interactions, and the safety of the drug are notable. One of these new anticonvulsants is pregabalin, a safe drug with almost no interaction with other antiepileptic drugs. Methods: In this open label clinical trial study, pregabalin was used for evaluation of its efficacy on reducing seizure frequency in 29 children suffering from refractory partial seizures.Average daily and weekly seizure frequency of the patients was recorded during a 6-week period (baseline period). Then, during a period of 2 weeks (titration period), pregabalin was started with a dose of 25-75 mg/d, using method of flexible dose, and was brought to maximum dose of drug that was intended in this study (450 mg/d) based on clinical response of the patients and seizure frequency. Then the patients were given the drug for 12 weeks and the average frequency of daily and weekly seizures were recorded again (treatment period). Findings : Reduction in seizure frequency in this study was 36% and the responder rate or number of patients who gained more than 50% reduction in seizure frequency was 51.7%. Conclusion: This study showed that pregabalin can be used with safety and an acceptable efficacy in treatment of childhood refractory partial seizures.Key Words: Pregabalin, Clinical trial, Refractory Partial Seizure, Seizure, Children     

Seizures, ataxia, developmental delay and the general paediatrician: glucose transporter 1 deficiency syndrome

AIM: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an important condition for the general paediatrician's differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1-DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4). METHODS: This is a review of eight Queensland patients with GLUT1-DS. The clinical presentation, clinical course, laboratory investigations and treatment outcomes are discussed. RESULTS: The clinical features noted in our patient cohort include combinations of ataxia, developmental delay and a severe seizure disorder that is refractory to anticonvulsant medications. Seizures are the most common clinical manifestation and may be exacerbated by phenobarbitone. The paired CSF: plasma glucose results ranged from 0.2 to 0.39 (normal <0.6) with an average of 0.33. 3-O-Methyl-D-Glucose uptake and GLUT1 Genotyping analysis have been performed on five patients thus far. Rapid and impressive seizure control was observed in 100% of our patients once the ketogenic diet was instituted, with half of the cohort being able to wean completely from anticonvulsants. CONCLUSION: Children presenting with a clinical phenotype consisting of a refractory seizure disorder, ataxia and developmental delay should prompt the consideration of Glucose transporter 1 deficiency syndrome. While the diagnostic test of lumbar puncture is an invasive manoeuvre, the diagnosis provides a viable treatment option, the ketogenic diet. GLUT1-DS displays clinical heterogeneity, but the value of early diagnosis and treatment is demonstrated by our patient cohort.