{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T11:33:27Z","timestamp":1776425607298,"version":"3.51.2"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Tuberous sclerosis complex (TSC) is a rare disease with a high risk of epilepsy and cognitive impairment in children. Ketogenic diet (KD) therapy has been consistently reported to be beneficial to TSC patients. In this study, we aimed to investigate the efficacy and safety of KD in the treatment of drug-resistant epilepsy and cognitive impairment in children with TSC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this multicenter study, 53 children (33 males and 20 females) with drug-resistant epilepsy or cognitive impairment caused by TSC were retrospectively recruited from 10 hospitals from January 1, 2010, to December 31, 2020. Intention-to-treat analysis was used to evaluate seizure reduction and cognition improvement as outcomes after KD therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 53 TSC patients included, 51 failed to be seizure-free with an average of 5.0 (range, 4\u20136) different anti-seizure medications (ASMs), before KD therapy. Although the other two patients achieved seizure freedom before KD, they still showed psychomotor development delay and electroencephalogram (EEG) abnormalities. At 1, 3, 6, and 12 months after the KD therapy, 51 (100%), 46 (90.2%), 35 (68.6%), and 16 patients (31.4%) remained on the diet therapy, respectively. At these time points, there were 26 (51.0%), 24 (47.1%), 22 (43.1%) and 13 patients (25.5%) having \u226550% reductions in seizure, including 11 (21.6%), 12 (23.5%), 9 (17.6%) and 3 patients (5.9%) achieving seizure freedom. In addition, of 51 patients with psychomotor retardation, 36 (36 of 51, 70.6%) showed cognitive and behavioral improvements. During the KD therapy, no serious side effects occurred in any patient. The most common side effects were gastrointestinal disturbance (20 of 53, 37.7%) and hyperlipidemia (6 of 53, 11.3%). The side effects were gradually relieved after adjustment of the ketogenic ratio and symptomatic treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>KD is an effective and safe treatment for TSC-related drug-resistant epilepsy and cognitive impairment in children. KD can reduce seizure frequency and may potentially improve cognition and behavior.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2022.863826","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T10:52:31Z","timestamp":1653389551000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["Ketogenic Diet Therapy for Drug-Resistant Epilepsy and Cognitive Impairment in Children With Tuberous Sclerosis Complex"],"prefix":"10.3389","volume":"13","author":[{"given":"Yu","family":"Fang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baomin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Zha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daoqi","family":"Mei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangbo","family":"Bian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junjie","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lifei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianxiang","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1590\/abd1806-4841.20186972","article-title":"Tuberous sclerosis complex: review based on new diagnostic criteria","volume":"93","author":"Portocarrero","year":"2018","journal-title":"An Bras Dermatol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.3389\/fneur.2019.01116","article-title":"Tuberous sclerosis complex (TSC): expert recommendations for provision of coordinated care","volume":"10","author":"Annear","year":"2019","journal-title":"Front Neurol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1146\/annurev-genom-083118-015354","article-title":"Genetic etiologies, diagnosis, and treatment of tuberous sclerosis complex","volume":"20","author":"Salussolia","year":"2019","journal-title":"Annu Rev Genomics Hum Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1177\/0883073817737446","article-title":"Predictors of drug-resistant epilepsy in tuberous sclerosis complex","volume":"32","author":"Jeong","year":"2017","journal-title":"J Child Neurol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1111\/j.1528-1167.2005.00266.x","article-title":"Tuberous sclerosis complex and the ketogenic diet","volume":"46","author":"Kossoff","year":"2005","journal-title":"Epilepsia."},{"key":"B6","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1007\/s00381-019-04066-7","article-title":"Factors affecting epilepsy prognosis in patients with tuberous sclerosis","volume":"35","author":"G\u00fcl Mert","year":"2019","journal-title":"Childs Nerv Syst."},{"key":"B7","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/s0887-8994(03)00407-7","article-title":"Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy","volume":"30","author":"Lazarowski","year":"2004","journal-title":"Pediatr Neurol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.pediatrneurol.2005.06.008","article-title":"New proteins configure a brain drug resistance map in tuberous sclerosis","volume":"34","author":"Lazarowski","year":"2006","journal-title":"Pediatr Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1002\/ajmg.c.31637","article-title":"A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND)","volume":"178","author":"de Vries","year":"2018","journal-title":"Am J Med Genet C Semin Med Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/s1474-4422(15)00069-1","article-title":"Neurological and neuropsychiatric aspects of tuberous sclerosis complex","volume":"14","author":"Curatolo","year":"2015","journal-title":"Lancet Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1177\/0883073809341272","article-title":"Attention-deficit hyperactivity disorder (ADHD) and tuberous sclerosis complex","volume":"24","author":"D'Agati","year":"2009","journal-title":"J Child Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1177\/0883073810361789","article-title":"Autism spectrum disorders in tuberous sclerosis: pathogenetic pathways and implications for treatment","volume":"25","author":"Curatolo","year":"2010","journal-title":"J Child Neurol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1097\/yco.0000000000000136","article-title":"Advances in the treatment of tuberous sclerosis complex","volume":"28","author":"Leclezio","year":"2015","journal-title":"Curr Opin Psychiatry."},{"key":"B14","doi-asserted-by":"publisher","first-page":"673583","DOI":"10.3389\/fneur.2021.673583","article-title":"Behavioral symptoms may correlate with the load and spatial location of tubers and with radial migration lines in tuberous sclerosis complex","volume":"12","author":"Cohen","year":"2021","journal-title":"Front Neurol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s11689-019-9289-6","article-title":"The role of glia in epilepsy, intellectual disability, and other neurodevelopmental disorders in tuberous sclerosis complex","volume":"11","author":"Wong","year":"2019","journal-title":"J Neurodev Disord."},{"key":"B16","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.seizure.2021.10.021","article-title":"Improving the effects of ketogenic diet therapy in children with drug-resistant epilepsy","volume":"94","author":"Yang","year":"2022","journal-title":"Seizure."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/j.1528-1167.2008.01821.x","article-title":"History of the ketogenic diet","volume":"49","author":"Wheless","year":"2008","journal-title":"Epilepsia."},{"key":"B18","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1080\/1028415x.2019.1627769","article-title":"Ketogenic diet: overview, types, and possible anti-seizure mechanisms","volume":"24","author":"Barzegar","year":"2021","journal-title":"Nutr Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1097\/wco.0000000000000432","article-title":"New insights into the mechanisms of the ketogenic diet","volume":"30","author":"Boison","year":"2017","journal-title":"Curr Opin Neurol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"23617","DOI":"10.1073\/pnas.2008980117","article-title":"Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling","volume":"117","author":"Warren","year":"2020","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B21","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/ejcn.2013.116","article-title":"Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets","volume":"67","author":"Paoli","year":"2013","journal-title":"Eur J Clin Nutr."},{"key":"B22","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.jalz.2018.12.017","article-title":"A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment","volume":"15","author":"Fortier","year":"2019","journal-title":"Alzheimers Dement."},{"key":"B23","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.pediatrneurol.2013.08.001","article-title":"Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference","volume":"49","author":"Northrup","year":"2013","journal-title":"Pediatr Neurol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.pediatrneurol.2021.07.011","article-title":"Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations","volume":"123","author":"Northrup","year":"2021","journal-title":"Pediatr Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","article-title":"Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE commission on therapeutic strategies","volume":"51","author":"Kwan","year":"2010","journal-title":"Epilepsia."},{"key":"B26","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1111\/epi.13670","article-title":"Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commission for classification and terminology","volume":"58","author":"Fisher","year":"2017","journal-title":"Epilepsia."},{"key":"B27","doi-asserted-by":"publisher","first-page":"45","DOI":"10.14581\/jer.17008","article-title":"Ketogenic diet for the management of epilepsy associated with tuberous sclerosis complex in children","volume":"7","author":"Park","year":"2017","journal-title":"J Epilepsy Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"106348","DOI":"10.1016\/j.eplepsyres.2020.106348","article-title":"Long-term outcomes of ketogenic diet in patients with tuberous sclerosis complex-derived epilepsy","volume":"164","author":"Youn","year":"2020","journal-title":"Epilepsy Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1093\/nutrit\/nuaa113","article-title":"Ketogenic diet and cognition in neurological diseases: a systematic review","volume":"79","author":"Pav\u00f3n","year":"2021","journal-title":"Nutr Rev."},{"key":"B30","doi-asserted-by":"publisher","first-page":"270","DOI":"10.18388\/pb.2020_342","article-title":"Ketogenic diet \u2013 mechanism of action and perspectives for the use in the therapy: data from clinical studies","volume":"66","author":"Pondel","year":"2020","journal-title":"Postepy Biochem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1093\/cercor\/bhw008","article-title":"Caloric restriction in older adults-differential effects of weight loss and reduced weight on brain structure and function","volume":"27","author":"Prehn","year":"2017","journal-title":"Cereb Cortex."},{"key":"B32","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.eplepsyres.2011.04.017","article-title":"The effects of the ketogenic diet on behavior and cognition","volume":"100","author":"Hallb\u00f6\u00f6k","year":"2012","journal-title":"Epilepsy Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1210\/jc.2015-2315","article-title":"Cognitive effects of intentional weight loss in elderly obese individuals with mild cognitive impairment","volume":"101","author":"Horie","year":"2016","journal-title":"J Clin Endocrinol Metab."},{"key":"B34","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1111\/j.1528-1167.2007.01025.x","article-title":"Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios\u2013comparison of 3:1 with 4:1 diet","volume":"48","author":"Seo","year":"2007","journal-title":"Epilepsia."},{"key":"B35","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1159\/000017390","article-title":"Path analysis shows that increasing ketogenic ratio, but not beta-hydroxybutyrate, elevates seizure threshold in the Rat","volume":"21","author":"Bough","year":"1999","journal-title":"Dev Neurosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1080\/14737175.2018.1428562","article-title":"mTOR dysregulation and tuberous sclerosis-related epilepsy","volume":"18","author":"Curatolo","year":"2018","journal-title":"Expert Rev Neurother."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e7","DOI":"10.1111\/j.1528-1167.2011.02981.x","article-title":"The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway","volume":"52","author":"McDaniel","year":"2011","journal-title":"Epilepsia."},{"key":"B38","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.braindev.2009.04.009","article-title":"Tumor growth in patients with tuberous sclerosis complex on the ketogenic diet","volume":"32","author":"Chu-Shore","year":"2010","journal-title":"Brain Dev."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.863826\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T10:52:34Z","timestamp":1653389554000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.863826\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,24]]},"references-count":38,"alternative-id":["10.3389\/fneur.2022.863826"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.863826","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,24]]},"article-number":"863826"}}