Applied nutritional investigationEffect of classic ketogenic diet treatment on lipoprotein subfractions in children and adolescents with refractory epilepsy
Introduction
Epilepsy is a neurologic disorder characterized by seizures that reflect abnormal electrical activity in one or more areas of the brain cortex [1]. The World Health Organization recently estimated that 0.7% of the population has epilepsy, representing 50 million people, with 80% living in developing countries [2].
Its etiology is associated with multiple structural and neurochemical dysfunctions, such as trauma, infectious diseases, congenital malformations, and genetic abnormalities [3]. These brain disorders result in neurobiologic, cognitive, psychological, and social consequences [1].
The majority of epilepsy treatment options is based on antiepileptic drugs; however, 20% to 30% of children with epilepsy have seizures refractory to these drugs. For these children and adolescents, the ketogenic diet (KD) has been indicated as a coadjuvant treatment [4], with consensus regarding its benefits for epilepsy control [5].
The KD is based on high-fat, low-carbohydrate, and moderate protein content distributed in a 4:1 or 3:1 (fat: carbohydrate and protein) ratio [4]. Therefore, fat catabolism is the primary source of energy and responsible for the production of ketone bodies, which have considerable involvement in the therapeutic mechanisms related to seizure control [6]. In addition to the clinical benefits associated with a significant reduction in epileptic seizures, the number and quantity of required antiepileptic drugs are generally decreased when initiating the KD [4].
However, the KD is associated with side effects such as hyperuricemia, hypocalcemia, metabolic acidosis, hypercholesterolemia, kidney stones, and gastrointestinal disorders (e.g., vomiting, diarrhea, and constipation) [4]. The main clinical sign is dyslipidemia [7], [8], and the primary changes in lipid metabolism are reflected as increased low-density lipoprotein cholesterol (LDL-C) and triacylglycerol (TG) levels.
Despite these recognized side effects, the literature did not describe the effect of the KD on physical lipoprotein properties in patients with refractory epilepsy. One study with healthy, normolipidemic adult men failed to report changes in TG, LDL-C, and oxidized LDL (oxLDL) levels after 6 wk on the KD [9]. However, individuals with a high proportion of small LDL particles had increased particle size related with higher LDL-1 concentrations. Compared with a low-fat diet, the use of the KD diet for 6 mo as a method for weight loss in adults resulted in reduced TG levels and increased large LDL and large HDL particles [10].
Additionally, there is a lack of prospective long-term studies that evaluate the effects of the KD on cardiovascular health in children with refractory epilepsy [11]. According to the Johns Hopkins University guidelines for dietary treatment of epilepsy in the United States, long-term changes in the lipid profile do not appear to be significant, but the influence of these changes on coronary heart disease are unknown [6].
Given this background, the goal of this study was to evaluate the effects of the classic KD on LDL and HDL subfractions in children and adolescents with refractory epilepsy.
Section snippets
Study design and participants
This prospective study was conducted from June 2012 to March 2014 at the Brazilian Reference Center–Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da USP. Children and adolescents of both sexes, aged 1 to 19 y, with epileptic seizures, independent of the etiology, refractory to multiple drugs, and for whom KD was indicated were included. Given the primary study focus on lipid metabolism, patients receiving hormone replacement therapy, using lipid-lowering drugs, or those
Results
Of the 52 patients who attended the group meeting, 38 children and adolescents were eligible (Fig. 1). The KD was not indicated for four patients because they had significant seizure control; another five were not included because they had diabetes mellitus, hypothyroidism, Down syndrome, or a combination of these diseases. An additional five patients refused KD treatment because they claimed they did not have good family and economic support. After baseline, 12 patients ceased the KD, and
Discussion
Although the present results confirmed the positive clinical benefits of the KD for the treatment of refractory epilepsy, they highlighted, for the first time, the negative effects of this diet on the qualitative aspects of lipoproteins. Small LDL particles migrate more easily to the subendothelial layer, where they are more susceptible to oxidation and other modifications, intensifying the atherogenicity of this lipoprotein [15]. It is currently accepted that these particles have a greater
Conclusion
Treatment using the KD had a negative effect on the lipid profile and contributed to a more atherogenic phenotype that involved generation of small LDL subfractions and smaller HDL size. However, we do not believe that the KD should be contraindicated for refractory epilepsy, and its clinical relevance should continue to be encouraged. However, results of the present study suggest that additional studies should be conducted that include a longer follow-up, cardiometabolic risk biomarkers, and
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Financial support for the study was received from the State of São Paulo Research Foundation (FAPESP # 2011/13616-4, 12/03775-0, 2012/20789-5 and 14/26094-4), National Institute for Science and Technology of Complex Fluids (INCT-FCx-USP, grant number: 573560/2008-0), and Group for Research on Complex Fluids (NAP-FCx-USP). The authors have no conflicts of interest to declare.