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This review summarizes the recent data and the current hypotheses on mechanisms that may contribute to drug\u2010resistant IGE. A literature search was conducted in PubMed and Embase for studies on mechanisms of drug resistance published since 1980. The literature shows neither consensus on the definition nor a widely accepted model to explain drug resistance in IGE or one of its subsyndromes. Large\u2010scale genetic studies have failed to identify distinct genetic causes or affected genes involved in pharmacokinetics. We found clinical and experimental evidence in support of four hypotheses: (1) \u201cnetwork hypothesis\u201d\u2014the degree of drug resistance in IGE reflects the severity of cortical network alterations, (2) \u201cminor focal lesion in a predisposed brain hypothesis\u201d\u2014minor cortical lesions are important for drug resistance, (3) \u201cinterneuron hypothesis\u201d\u2014impaired functioning of \u03b3\u2010aminobutyric acidergic interneurons contributes to drug resistance, and (4) \u201cchanges in drug kinetics\u201d\u2014genetically impaired kinetics of antiseizure medication (ASM) reduce the effectiveness of available ASMs. In summary, the exact definition and cause of drug resistance in IGE is unknown. However, published evidence suggests four different mechanisms that may warrant further investigation.<\/jats:p>","DOI":"10.1111\/epi.17410","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T11:18:38Z","timestamp":1663154318000},"page":"3007-3019","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Drug resistance in idiopathic generalized epilepsies: Evidence and concepts"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0546-4619","authenticated-orcid":false,"given":"Joanna","family":"Gesche","sequence":"first","affiliation":[{"name":"Department of Neurology Odense University Hospital  Odense Denmark"},{"name":"Department of Clinical Research University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8268-1492","authenticated-orcid":false,"given":"Christoph 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