Longitudinal changes in insulin resistance in children with epilepsy on ketogenic diet: Prevalence and risk factors☆
Introduction
Antiepileptic drugs (AEDs) are used for treating epilepsy and other diseases, including psychiatric disorders, neuropathic pain, and migraine. Long-term therapy with AEDs for patients with epilepsy has long been associated with adverse metabolic effects. Several studies have reported an association between weight gain, hyperinsulinemia, and increased insulin resistance (IR) and various metabolic and endocrine abnormalities in patients receiving valproate [1,2]. Other studies have reported dyslipidemia and an increased risk of atherosclerosis in patients receiving carbamazepine [3]. Subsequently, abnormal glucose tolerance, hyperinsulinemia, dyslipidemia, and hypertension are the classical symptoms of IR, summarized as metabolic syndrome [4]. Since metabolic syndrome is associated with an increased risk of cardiovascular diseases, a drug-induced increase in IR may be harmful in patients under long-term treatment with AEDs. Insulin resistance is a condition in which the adequate promotion of peripheral glucose disposal, inhibition of hepatic glucose production, and inhibition of hepatic glucose-induced production of low-density lipoproteins under normal plasma insulin levels is impaired [5,6]. This results in lipid accumulation and non-alcoholic fatty liver disease. Metabolic or endocrine adverse effects, such as IR and hyperinsulinemia, have not been reported for the newer AEDs to date [7].
The ketogenic diet (KD) is a well-established nonpharmacologic treatment used for children and adults with medically refractory epilepsy. The KD was introduced in 1921, and its broad-spectrum efficacy has been document [8]; however, the adverse effects associated with KT include gastrointestinal disturbances, weight loss, and hyperlipidemia. Other side effects may potentially develop owing to vitamin and mineral deficiencies (e.g., osteopenia, osteoporosis, and cardiomyopathy) [9]. The dietary habits and quality of nutrition during childhood may play crucial roles in the development of IR and prevention of the onset of pathological IR through consumption of a diet rich in macronutrients, micronutrients, fiber, and vegetables and with reduced saturated fat content [10].
To the best of our knowledge, previous studies have not evaluated the longitudinal changes in IR in children with epilepsy on a KD. Therefore, this study aimed to (1) assess the longitudinal changes in IR in children with epilepsy on KD therapy and (2) evaluate the potential risk factors associated with the aggravation of IR during the KD therapy in a single tertiary pediatric epilepsy clinic.
Section snippets
Patients
We conducted a retrospective longitudinal cohort study involving children on a KD for the treatment of their epilepsy between January 2013 and December 2017 at a pediatric neurology clinic affiliated with Pusan National University Children's Hospital. The inclusion criteria were as follows: (a) age < 16 years, (b) follow-up of at least 6 months after the initiation of the KD therapy, (c) ketosis identified based on the ketone levels measured in the urine and serum during the KD therapy, and (d)
HOMA-IR status and longitudinal changes from baseline to the last follow-up
Twenty-eight children were included in this study. The demographic profiles of the patients are presented in Table 1. Seventeen (60.7%) patients were boys. The patients' age at the initiation of the KD therapy ranged from 0.5 to 9.9 years, with a median age of 2.7 ± 2.4 years. The median duration of the KD therapy was 2.1 ± 1.4 years. Before the initiation of the KD, the baseline median HOMA-IR (HOMA-IR-1) value for all patients was 1.2 ± 0.2. The median HOMA-IR value at the last follow-up
Discussion
In the current retrospective longitudinal cohort study, the median HOMA-IR value before the initiation of the KD therapy in 28 children with epilepsy was 1.2 ± 0.2 and that at the last follow-up was 1.8 ± 0.3, showing a significant increase (0.6 ± 0.3, p < 0.001). Patients with a significantly higher HOMA-IR value (group A, HOMA-IR-2 ≥ 1.9) presented with the following associated factors: younger median age at seizure onset (p < 0.001), at the initiation of the AEDs (p < 0.001), and at the
Conclusion
We noticed that the longitudinal increase in IR, from the baseline to the last follow-up, was significant during the KD therapy in children with medically intractable epilepsy. Younger age at seizure onset, at the initiation of the AEDs, and at the initiation of the KD therapy and higher serum LDL-C and triglyceride levels were the potential independent risk factors for the longitudinal increase in IR. Close monitoring of the serum lipid levels, especially at younger age, can aid in detecting
Disclosure of funding for research
We declare no financial relationships relevant to this article.
Author statement
All authors affirm that the work described is consistent with the guidelines for ethical publications of Epilepsy and Behavior. All authors have made a significant contribution to this study and in the preparation of the manuscript, have approved the final version for submission, and accept responsibility for its content. Unnamed groups or persons did not have a primary role in the study or manuscript preparation.
Ethical publication statement
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Declaration of competing interest
The authors declare that they have no conflicts of interest.
Acknowledgment
This study was supported by the Research Institute for Convergence of Biomedical Science and Technology Grant, Pusan National University Yangsan Hospital. We would like to thank Editage (www.editage.co.kr) for English language editing.
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Author Contributions
Y-J.L. and J.K. (primary investigators) conceptualized and designed the study, drafted the initial manuscript, and approved the final manuscript, as submitted. SO.N. coordinated the study, supervised data collection, critically reviewed the manuscript, and approved the final manuscript, as submitted. AK, SY.B., and TJ.L. were responsible for the recruitment and performed examinations. YM.K., GM.Y., and JW.C. carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript, as submitted.