Article

A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy

UCL-Institute of Child Health & Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
Epilepsia (Impact Factor: 4.57). 12/2008; 50(5):1109-17. DOI: 10.1111/j.1528-1167.2008.01870.x
Source: PubMed

ABSTRACT

To conduct the first randomized trial on classical and medium-chain triglyceride (MCT) versions of the ketogenic diet, examining efficacy and tolerability after 3, 6, and 12 months.
One hundred forty-five children with intractable epilepsy were randomized to receive a classical or an MCT diet. Seizure frequency was assessed after 3, 6, and 12 months. Treatment withdrawals were documented. Tolerability was assessed by questionnaire, and blood ketone levels were measured.
Of the 61 children who started a classical diet and the 64 who started an MCT diet, data from 94 were available for analysis: 45 classical and 49 MCT. After 3, 6, and 12 months there were no statistically significant differences in mean percentage of baseline seizures between the two groups (3 months: classical 66.5%, MCT 68.9%; 6 months: classical 48.5%, MCT 67.6%; 12 months: classical 40.8%, MCT 53.2%; all p > 0.05). There were no significant differences between groups in numbers achieving greater than 50% or 90% seizure reduction. Serum acetoacetate and beta-hydroxybutyrate levels at 3 and 6 months were significantly higher in children on the classical diet (p < 0.01); this was the case at 12 months for acetoacetate. There were no significant differences in tolerability except increased reports in the classical group of lack of energy after 3 months and vomiting after 12 months.
This study has shown classical and MCT ketogenic diet protocols to be comparable in efficacy and tolerability; both ways of implementing the diet have their place in the treatment of childhood epilepsy.

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    • "Another well-known form of the KD is the MCTdiet , which consists mainly of medium-chain triglycerides (MCTs). The randomized controlled trial of Neal et al. showed that the classical diet did not have any advantage over the MCT-diet in terms of efficacy and tolerability [2]. In a recent Cochrane review, authors concluded that despite the heterogeneity, all trials showed that at least 38% of the patients had a 50% reduction in seizure frequency compared to controls at three months, and this response was maintained for up to a year [3]. "
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    ABSTRACT: The present study assessed the long-term (i.e., 24months) efficacy of the ketogenic diet (KD) as an add-on therapy in children with refractory epilepsy, with focus on seizure frequency, seizure severity, and tolerability. Most patients were treated with the MCT-diet. At one and two years, 33% and 23%, respectively, of the 48 included patients were still on the KD. After three months, one year, and two years of treatment, 16.7% of the patients were responders. The highest responder rate (i.e., 22.9%) was seen at six and nine months of treatment. Of the fifteen patients with seizure clusters during baseline, 60% were responders after three months when looking at cluster reduction and most of them were not responders for the total seizure frequency. From three months of treatment onwards, most of the patients had a relevant decrease in seizure severity which was mainly related to the most severe seizure type. Gastrointestinal dysfunction was often reported, especially in the first six weeks of treatment. Growth deceleration was present in 30% of the patients, and weight reduction in 15%. Improved arousal was mentioned in 30% of patients. No patients developed ECG abnormalities or kidney stones. Increase in lipid profile was rare. The KD is an effective therapy for children with therapy-resistant epilepsy. Effectiveness is reflected in the reduction of seizure frequency as well as in the reduction of seizure severity. After 6months of treatment, it is obvious which patients are responders and tolerate the treatment well. Most of these patients will continue to benefit from the KD for a longer time. Long-term use of the diet was well tolerated. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Epilepsy & Behavior
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    • "The exact mechanism by which caprylic acid exerts its acute anticonvulsant effects remains, however, unknown. Over the years, the efficacy of both the classic and the MCT ketogenic diets has been proven in a number of clinical trials (Freeman et al., 2007; Kossoff and Rho, 2009; Liu and Wang, 2013; Neal et al., 2009; Payne et al., 2011). Although the ketogenic diet has been in use for almost a century, the mechanism underlying its anti-seizure effects is still poorly understood. "
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    ABSTRACT: Although several studies have reported the acute anticonvulsant activity of caprylic acid in animal seizure models, little is known about the mechanism underlying this effect. Recently, the role of adenosine in the efficacy of the ketogenic diet has been postulated. Therefore, the present study aimed to evaluate the possible involvement of the adenosine system (in non-fasted mice) as well as the role of glucose restriction (in fasted and non-fasted mice) in the acute anticonvulsant activity of caprylic acid in the 6 Hz psychomotor seizure threshold test. We showed that the anticonvulsant effect of caprylic acid (30 mmol/kg, p.o.) was reversed by a selective adenosine A(1) receptor antagonist (DPCPX, 1 mg/kg, i.p.) and a selective adenosine A(2A) receptor antagonist (KW-6002, 1 mg/kg, p.o.) but not by glibenclamide (1 pg/mouse, i.c.v.) - the ATP-sensitive potassium (K-ATP) channel blocker. Co-administration of an ineffective dose of caprylic acid (20 mmol/kg) with an ineffective dose of adenosine transporter inhibitor (dipyridamole, 50 mg/kg, i.p.) significantly raised the threshold for the 6 Hz-induced seizures. A high dose of glucose (2 g/kg) significantly only diminished the anticonvulsant effect of caprylic acid (30 mmol/kg) in non-fasted mice, and this was accompanied by an increase in blood glucose level and no changes in ketone body level as compared to the caprylic acid-treated group. In both fasted and non-fasted mice treated with glucose and caprylic acid, a significant decrease in trunk blood pH occurred as compared to the control group. No alternations in motor coordination or muscular strength were noted with any drug treatment, apart from the caprylic acid and glibenclamide combination, where a significant decrease in the muscle strength was observed. The present study provides a new insight into the role of the adenosine system and low glucose usage in the mechanisms underlying the anticonvulsant effects of caprylic acid in the 6 Hz seizure test
    Full-text · Article · Mar 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "The exact mechanism by which caprylic acid exerts its acute anticonvulsant effects remains, however, unknown. Over the years, the efficacy of both the classic and the MCT ketogenic diets has been proven in a number of clinical trials (Freeman et al., 2007; Kossoff and Rho, 2009; Liu and Wang, 2013; Neal et al., 2009; Payne et al., 2011). Although the ketogenic diet has been in use for almost a century, the mechanism underlying its anti-seizure effects is still poorly understood. "
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    ABSTRACT: Capric acid (CA10) is a 10-carbon medium-chain fatty acid abundant in the medium-chain triglyceride ketogenic diet (MCT KD). The purpose of this study was to characterize acute anticonvulsant effects of CA10 across several seizure tests in mice. Anticonvulsant effects of orally (p.o.) administered CA10 were assessed in the maximal electroshock seizure threshold (MEST), 6-Hz seizure threshold, and intravenous pentylenetetrazole (i.v. PTZ) seizure tests in mice. Acute effects of CA10 on motor coordination were assessed in the grip and chimney tests. Plasma and brain concentrations of CA10 were measured. Co-administration studies with CA10 and another abundant medium-chain fatty acid, caprylic acid (CA8) were performed. CA10 showed significant and dose-dependent anticonvulsant properties by increasing seizure thresholds in the 6-Hz and MEST seizure tests; it was ineffective in the i.v. PTZ seizure test. At higher doses than those effective in the 6-Hz and MEST seizure tests, CA10 impaired motor performance in the grip and chimney tests. An enhanced anticonvulsant response in the 6-Hz seizure test was produced when CA8 and CA10 were co-administered. An acute p.o. administration of CA10 resulted in dose-proportional increases in its plasma and brain concentrations. CA10 exerted acute anticonvulsant effects at doses that produce plasma exposures comparable to those reported in epileptic patients on the MCT KD. An enhanced anticonvulsant effect is observed when CA10 and the other main constituent of the MCT KD, CA8, were co-administered. Thus, acute anticonvulsant properties of CA10 and CA8 may influence the overall clinical efficacy of the MCT KD. Copyright © 2014. Published by Elsevier Inc.
    Full-text · Article · Oct 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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