Advances in medium-chain triglyceride ketogenic diet for refractory epilepsy_Journal of Epilepsy

Authors：

DU Taotao ¹ , BI Jinyu ² , LUO Chenyu ^1,2 ,  SUN Meizhen ^1,2

1. Shanxi Medical University, Taiyuan 030000, China;
2. Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan 030000, China;

Corresponding author：

SUN Meizhen, Email: sunmeizhen213@126.com

Keywords：

Medium-chain triglyceride; Ketogenic diet; Refractory epilepsy; Mechanism; Effect

DOI：

10.7507/2096-0247.202306004

Video：

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Ketogenic diet (KD) is one of the effective treatments for refractory epilepsy (RE) and is recommended when anti-seizure medications (ASMs) are ineffective or less effective, inoperable or ineffective. The efficacy of the medium-chain triglyceride (MCT) ketogenic diet is as good as the classical KD (CKD), which has been demonstrated in several retrospective, prospective, and randomized studies, and MCT is more ketogenic than long-chain triglycerides, so MCTD allows more carbohydrate and protein foods, which makes MCTD more palatable than CKD more palatable. Research advances in the mechanisms and clinical efficacy associated with MCTD in the treatment of refractory epilepsy are reviewed.

Citation： DU Taotao, BI Jinyu, LUO Chenyu, SUN Meizhen. Advances in medium-chain triglyceride ketogenic diet for refractory epilepsy. Journal of Epilepsy, 2023, 9(5): 406-410. doi: 10.7507/2096-0247.202306004 Copy

1.	陈玲, 黄浩. 难治性癫痫相关发病机制及研究进展. 中华老年心脑血管病杂志, 2021, 23(6): 670-672.
2.	Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology, 1971, 21: 1097-1103.
3.	Neal E. “Alternative” ketogenic diets. In: Masino SA, ed. Ketogenic diet and metabolic therapies. New York: Oxford University Press, 2017: 5-15.
4.	Augustin K, Khabbush A, Williams S, et al. Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol, 2018 , 17(1): 84-93.
5.	Nimbkar S, Leena MM, Moses JA, et al. Medium chain triglycerides (MCT): State-of-the-art on chemistry, synthesis, health benefits and applications in food industry. Compr Rev Food Sci Food Saf, 2022 , 21(2): 843-867.
6.	Schonfeld P, Wojtczak L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res, 2016, 57: 943-954.
7.	张星弛, 韩培涛, 李晓莉, 等. 中链甘油三酯的研究进展. 食品研究与开发, 2017, 38(23): 220-224.
8.	Lei E, Vacy K, Boon WC. Fatty acids and their therapeutic potential in neurological disorders. Neurochemistry International, 2016, 95: 75-84.
9.	Wlaz P, Socala K, Nieoczym D, et al. Acute anticonvulsant effects of capric acid in seizure tests in mice. Prog Neuropsychopharmacol Biol Psychiatry, 2015, 57: 110-116.
10.	Oldendorf WH. Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids. Am J Physiol, 1973, 224: 1450-1453.
11.	Chang P, Augustin K, Boddum K, et al. Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain, 2016, 139: 431-443.
12.	Simeone TA, Matthews SA, Samson KK, et al. Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy. Exp Neurol, 2017, 287: 54-64.
13.	Warren EC, Dooves S, Lugarà E, et al. Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling. Proc Natl Acad Sci USA, 2020, 117: 23617-23625.
14.	Chang P, Terbach N, Plant N, et al. Seizure control by ketogenic diet-associated medium chain fatty acids. Neuropharmacology, 69: 105-114.
15.	Chang P, Zuckermann AM, Williams S, et al. Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency. J Pharmacol Exp Ther, 2015 , 352(1): 43-52.
16.	Eid T, Ghosh A, Wang Y, et al. Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. Brain, 2008, 131: 2061-2070.
17.	Andersen JV, Westi EW, Jakobsen E, et al. Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply. Mol Brain, 2021, 14(1): 132.
18.	Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci, 2013, 36: 32-40.
19.	Li J, O’Leary EI, Tanner GR. The ketogenic diet metabolite beta-hydroxybutyrate (beta-HB) reduces incidence of seizure-like activity (SLA) in a Katp-and GABAb-dependent manner in a whole-animal Drosophila melanogaster model. Epilepsy Res, 2017, 133: 6-9.
20.	Barzegar M, Afghan M, Tarmahi V, et al. Ketogenic diet: overview, types, and possible anti-seizure mechanisms. Nutr Neurosci, 2021, 24(4): 307-316.
21.	Tanner GR, Lutas A, Martinez-Francois JR, et al. Single KATP channel opening in response to action potential firing in mouse dentate granule neurons. J Neurosci, 2011, 31: 8689-8696.
22.	Cunha RA. Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade. Purinergic Signal, 2005, 1: 111-134.
23.	Kim do Y, Simeone KA, Simeone TA, et al. Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann Neurol, 2015, 78: 77-87.
24.	Olson CA, Vuong HE, Yano JM, et al. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell, 2018, 173: 1728-1741.
25.	Pilla R, Law TH, Pan Y, et al. The Effects of a ketogenic medium-chain triglyceride diet on the feces in dogs with idiopathic epilepsy. Front Vet Sci, 2020, 22(7): 541-547.
26.	Han FY, Conboy-Schmidt L, Rybachuk G, et al. Dietary medium chain triglycerides for management of epilepsy: New data from human, dog, and rodent studies. Epilepsia, 2021, 62(8): 1790-1806.
27.	Neal EG, Hannah Chaffe, Ruby H. Schwartz, et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia, 2010, 50(5): 1109-1117.
28.	Liu YM, Wang HS. Medium-chain triglyceride ketogenic diet, an effective treatment for drug-resistant epilepsy and a comparison with other ketogenic diets. Biomed J, 2013, 36(1): 9-15.
29.	Liu YMC, Haw A, Campbell K, et al. A prospective 12 months study: growth and lipid status of children treated with the classic and medium-chain triglyceride ketogenic diets. Epilepsia, 2007, 47(1): 141- 142.
30.	Liu YMC, Williams S, Basualdo-Hammond C, et al. A prospective study: growth and nutritional status of children treated with the ketogenic diet. J Am Diet Assoc, 2019, 103: 707-712.
31.	Baba N, Bracco EF, Hashim SA. Enhanced thermogenesis and diminished deposition of fat in response to overfeeding with diet containing medium chain triglyceride. The American Journal of Clinical Nutrition, 1982, 35(4): 678-682.
32.	Nur Izzati Zulkanain , Sharaniza Ab-Rahim , Siti Nazrina Camalxaman , et al. Medium-chain fatty acids in nutritional therapy: a review. Malaysian Journal of Fundamental and Applied Sciences, 2020, 16(3) : 318-323.
33.	Schoeler NE, Orford M, Vivekananda U, et al. K. Vita: a feasibility study of a blend of medium chain triglycerides to manage drug-resistant epilepsy. Brain Commun, 2021, 3(4): 160.
34.	生酮饮食疗法在癫痫及相关神经系统疾病中的应用专家共识. 中华儿科杂志, 2019, 30(11): 820-825.
35.	Groesbeck DK. Bluml RM, Kossoff EH. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol, 2006, 48: 978-981.

1. 陈玲, 黄浩. 难治性癫痫相关发病机制及研究进展. 中华老年心脑血管病杂志, 2021, 23(6): 670-672.
2. Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology, 1971, 21: 1097-1103.
3. Neal E. “Alternative” ketogenic diets. In: Masino SA, ed. Ketogenic diet and metabolic therapies. New York: Oxford University Press, 2017: 5-15.
4. Augustin K, Khabbush A, Williams S, et al. Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol, 2018 , 17(1): 84-93.
5. Nimbkar S, Leena MM, Moses JA, et al. Medium chain triglycerides (MCT): State-of-the-art on chemistry, synthesis, health benefits and applications in food industry. Compr Rev Food Sci Food Saf, 2022 , 21(2): 843-867.
6. Schonfeld P, Wojtczak L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res, 2016, 57: 943-954.
7. 张星弛, 韩培涛, 李晓莉, 等. 中链甘油三酯的研究进展. 食品研究与开发, 2017, 38(23): 220-224.
8. Lei E, Vacy K, Boon WC. Fatty acids and their therapeutic potential in neurological disorders. Neurochemistry International, 2016, 95: 75-84.
9. Wlaz P, Socala K, Nieoczym D, et al. Acute anticonvulsant effects of capric acid in seizure tests in mice. Prog Neuropsychopharmacol Biol Psychiatry, 2015, 57: 110-116.
10. Oldendorf WH. Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids. Am J Physiol, 1973, 224: 1450-1453.
11. Chang P, Augustin K, Boddum K, et al. Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain, 2016, 139: 431-443.
12. Simeone TA, Matthews SA, Samson KK, et al. Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy. Exp Neurol, 2017, 287: 54-64.
13. Warren EC, Dooves S, Lugarà E, et al. Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling. Proc Natl Acad Sci USA, 2020, 117: 23617-23625.
14. Chang P, Terbach N, Plant N, et al. Seizure control by ketogenic diet-associated medium chain fatty acids. Neuropharmacology, 69: 105-114.
15. Chang P, Zuckermann AM, Williams S, et al. Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency. J Pharmacol Exp Ther, 2015 , 352(1): 43-52.
16. Eid T, Ghosh A, Wang Y, et al. Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. Brain, 2008, 131: 2061-2070.
17. Andersen JV, Westi EW, Jakobsen E, et al. Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply. Mol Brain, 2021, 14(1): 132.
18. Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci, 2013, 36: 32-40.
19. Li J, O’Leary EI, Tanner GR. The ketogenic diet metabolite beta-hydroxybutyrate (beta-HB) reduces incidence of seizure-like activity (SLA) in a Katp-and GABAb-dependent manner in a whole-animal Drosophila melanogaster model. Epilepsy Res, 2017, 133: 6-9.
20. Barzegar M, Afghan M, Tarmahi V, et al. Ketogenic diet: overview, types, and possible anti-seizure mechanisms. Nutr Neurosci, 2021, 24(4): 307-316.
21. Tanner GR, Lutas A, Martinez-Francois JR, et al. Single KATP channel opening in response to action potential firing in mouse dentate granule neurons. J Neurosci, 2011, 31: 8689-8696.
22. Cunha RA. Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade. Purinergic Signal, 2005, 1: 111-134.
23. Kim do Y, Simeone KA, Simeone TA, et al. Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann Neurol, 2015, 78: 77-87.
24. Olson CA, Vuong HE, Yano JM, et al. The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell, 2018, 173: 1728-1741.
25. Pilla R, Law TH, Pan Y, et al. The Effects of a ketogenic medium-chain triglyceride diet on the feces in dogs with idiopathic epilepsy. Front Vet Sci, 2020, 22(7): 541-547.
26. Han FY, Conboy-Schmidt L, Rybachuk G, et al. Dietary medium chain triglycerides for management of epilepsy: New data from human, dog, and rodent studies. Epilepsia, 2021, 62(8): 1790-1806.
27. Neal EG, Hannah Chaffe, Ruby H. Schwartz, et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia, 2010, 50(5): 1109-1117.
28. Liu YM, Wang HS. Medium-chain triglyceride ketogenic diet, an effective treatment for drug-resistant epilepsy and a comparison with other ketogenic diets. Biomed J, 2013, 36(1): 9-15.
29. Liu YMC, Haw A, Campbell K, et al. A prospective 12 months study: growth and lipid status of children treated with the classic and medium-chain triglyceride ketogenic diets. Epilepsia, 2007, 47(1): 141- 142.
30. Liu YMC, Williams S, Basualdo-Hammond C, et al. A prospective study: growth and nutritional status of children treated with the ketogenic diet. J Am Diet Assoc, 2019, 103: 707-712.
31. Baba N, Bracco EF, Hashim SA. Enhanced thermogenesis and diminished deposition of fat in response to overfeeding with diet containing medium chain triglyceride. The American Journal of Clinical Nutrition, 1982, 35(4): 678-682.
32. Nur Izzati Zulkanain , Sharaniza Ab-Rahim , Siti Nazrina Camalxaman , et al. Medium-chain fatty acids in nutritional therapy: a review. Malaysian Journal of Fundamental and Applied Sciences, 2020, 16(3) : 318-323.
33. Schoeler NE, Orford M, Vivekananda U, et al. K. Vita: a feasibility study of a blend of medium chain triglycerides to manage drug-resistant epilepsy. Brain Commun, 2021, 3(4): 160.
34. 生酮饮食疗法在癫痫及相关神经系统疾病中的应用专家共识. 中华儿科杂志, 2019, 30(11): 820-825.
35. Groesbeck DK. Bluml RM, Kossoff EH. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol, 2006, 48: 978-981.

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