{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T22:24:06Z","timestamp":1773527046829,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epileptic Disorders"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The ketogenic diet (KD) is the standard treatment for glucose transporter type 1 deficiency syndrome (GLUT1\u2010DS), typically yielding seizure reduction and cognitive\/motor gains. However, a small subset of patients shows limited or no clinical benefit. This phenomenon, referred to as \u201cKD resistance,\u201d remains poorly understood and inconsistently defined. We propose a working definition, outline evaluation domains, summarize candidate mechanisms, and indicate management steps.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Narrative review of published evidence and expert opinion across clinical, biochemical, EEG, and adherence domains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>KD resistance may be considered when all are present: (1) confirmed therapeutic ketosis (serial blood \u03b2\u2010hydroxybutyrate \u22652.0\u20132.5\u2009mmol\/L on repeated measurements); (2) adequate dietary adherence verified by dietetic assessment and, when available, validated tools; (3) sufficient trial duration (\u22653\u2009months; longer for primarily cognitive\/motor goals); and (4) lack of meaningful improvement on symptom\u2010relevant standardized measures. EEG interictal epileptiform discharge burden can be used as an adjunct marker but is not required. KD resistance may involve several dimensions: failure to achieve therapeutic ketosis, lack of symptom improvement despite confirmed ketosis, or challenges with adherence that limit efficacy. Possible contributing factors include genotypic variability in SLC2A1, mitochondrial dysfunction, impaired blood\u2013brain barrier transport, hormonal influences, and epigenetic regulation. We outline a multidomain evaluation framework with suggested metrics, summarize candidate mechanisms (ketone transport\/utilization, mitochondrial function, neurotransmission, ion channels\/neuromodulators, inflammation\/oxidative stress, epigenetic regulation), and indicate when to introduce a KD\u2010compatible anti\u2010seizure medication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>The proposed definition and framework standardize terminology and reporting, guide decisions for suboptimal responders, and set priorities for multicenter validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epd2.70107","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T14:45:02Z","timestamp":1759243502000},"page":"1247-1254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Toward a working definition of ketogenic diet resistance in\n                    <scp>GLUT1<\/scp>\n                    deficiency syndrome"],"prefix":"10.1002","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4482-3506","authenticated-orcid":false,"given":"Raffaele","family":"Falsaperla","sequence":"first","affiliation":[{"name":"Department of Medical Sciences\u2010Pediatric Section University of Ferrara  Ferrara Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Sortino","sequence":"additional","affiliation":[{"name":"Unit of Pediatrics and Pediatric Emergency Azienda Ospedaliero\u2010Universitaria Policlinico \u201cRodolico\u2010San Marco,\u201d San Marco Hospital, University of Catania  Catania Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard Josef","family":"Kluger","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Institute of Rehabilitation, Transition and Palliation of Neurologically Ill Children, Paracelsus Medical University  Salzburg Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Herberhold","sequence":"additional","affiliation":[{"name":"Clinic for Neuropediatrics and Neurorehabilitation Epilepsy Center for Children and Adolescents, Sch\u00f6n Klinik Vogtareuth  Vogtareuth Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"R\u00fcegger","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics University Children's Hospital Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[{"name":"Pediatric Neurology and Muscular Diseases Unit IRCCS Istituto Giannina Gaslini, Full Member of ERN\u2010Epicare  Genoa Italy"},{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genova  Genoa Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martino","family":"Ruggieri","sequence":"additional","affiliation":[{"name":"Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry University of Catania  Catania Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joerg","family":"Klepper","sequence":"additional","affiliation":[{"name":"Klinikum Aschaffenburg\u2010Alzenau  Aschaffenburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7931-2327","authenticated-orcid":false,"given":"Georgia","family":"Ramantani","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics University Children's Hospital Zurich  Zurich Switzerland"},{"name":"University of Zurich  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2007.00707.x"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awp336"},{"key":"e_1_2_13_4_1","volume-title":"GeneReviews\u00ae","author":"Wang D","year":"1993"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.1224"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12414"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2008.01821.x"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.12096"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2016.01.011"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.05302.x"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2005-872843"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073814531822"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/epd2.20063"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.26574\/maedica.2019.14.2.93"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2011.02.007"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2011.03961.x"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2014.08.015"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2019.02.012"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.13110"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12225"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2024.05.010"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/foods12173214"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0042-1755343"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu15173673"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu12061809"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17777"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2017.09.005"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18013"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.145789"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-022-02513-4"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073813488671"}],"container-title":["Epileptic Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epd2.70107","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/epd2.70107","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epd2.70107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:01:28Z","timestamp":1773010888000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epd2.70107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":30,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/epd2.70107"],"URL":"https:\/\/doi.org\/10.1002\/epd2.70107","archive":["Portico"],"relation":{},"ISSN":["1294-9361","1950-6945"],"issn-type":[{"value":"1294-9361","type":"print"},{"value":"1950-6945","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,30]]},"assertion":[{"value":"2025-07-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}