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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ETranslational and scientific advances in epilepsy over recent decades have directly impacted patient care, but much still remains unknown. The identification of a genetic basis of a form of epilepsy and a description of how an agent, quinidine, with in vitro efficacy provided effective treatment for a patient in the clinical setting are presented.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eepilepsy\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EEpilepsy Phenome\/Genome Project\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EEpi4K\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Equinidine\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EKCNT1 mutation\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eepileptic encephalopathies\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eepisodic \u0026amp; paroxysmal disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EWhen patients seek the help of a physician, they ask 3 universal questions:\u003C\/p\u003E\n         \u003Cul class=\u0022list-unord \u0022 id=\u0022list-1\u0022\u003E\u003Cli id=\u0022list-item-1\u0022\u003E\n               \u003Cp id=\u0022p-3\u0022\u003EWhy did this happen to me?\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-2\u0022\u003E\n               \u003Cp id=\u0022p-4\u0022\u003ECan you help me?\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-3\u0022\u003E\n               \u003Cp id=\u0022p-5\u0022\u003EWhat does my future hold?\u003C\/p\u003E\n            \u003C\/li\u003E\u003C\/ul\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EYet, for patients with epilepsy, typically all 3 of these questions remain mostly unanswered, despite advances in the field in recent decades, according to Daniel H. Lowenstein, MD, University of California, San Francisco Medical Center, San Francisco, California, USA. He noted that, although treatments are available for epilepsy, treatment selection and whether it will be effective in a patient too often remain an \u201ceducated guess.\u201d And for most patients, both the cause of epilepsy and their prognosis remain unknown.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ETherapeutic Advances\u003C\/h2\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EDr Lowenstein noted that at least 15 new agents have entered the market with FDA approval since the mid-1970s, but the overall evidence suggests that these new therapies have not significantly impacted patient care [Schmidt D, Sillanp\u00e4\u00e4 M. \u003Cem\u003ENeurology\u003C\/em\u003E. 2012; L\u00f6scher W, Schmidt D. \u003Cem\u003EEpilepsia\u003C\/em\u003E. 2011; Shorvon SD. \u003Cem\u003EEpilepsia\u003C\/em\u003E. 2009]. Although drug regimens have simplified over the years for patients with epilepsy (which has led to the appearance that more patients may tolerate these drugs and do better on them), the evidence to support these observations is very weak. This was demonstrated by the SANAD trial, one of the largest studies to evaluate drug treatment of new onset epilepsy [Marson AG et al. \u003Cem\u003EHealth Technol Assess\u003C\/em\u003E. 2007]. SANAD compared the efficacy and tolerability of new drugs with carbamazepine and valproate in \u0026gt;\u20052400 patients and demonstrated no significant difference between the newer and second generation agents.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ETranslational Advances\u003C\/h2\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EIn contrast, however, Dr Lowenstein emphasized that significant translational advances have occurred in the past 50 years, with a direct impact on patient care in epilepsy. These have been in the areas of\u003C\/p\u003E\n         \u003Cul class=\u0022list-unord \u0022 id=\u0022list-2\u0022\u003E\u003Cli id=\u0022list-item-4\u0022\u003E\n               \u003Cp id=\u0022p-9\u0022\u003Eneuronal physiology during seizures, in particular with respect to demonstration of the paroxysmal depolarization shift that occurs in neurons in epilepsy;\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-5\u0022\u003E\n               \u003Cp id=\u0022p-10\u0022\u003Eunderstanding the molecular, cellular, and network characteristics of absence epilepsy;\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-6\u0022\u003E\n               \u003Cp id=\u0022p-11\u0022\u003Eneuronal injury caused by prolonged seizures;\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-7\u0022\u003E\n               \u003Cp id=\u0022p-12\u0022\u003Evideo electroencephalogram (EEG) telemetry, which has advanced the diagnostic capabilities in epilepsy and the ability to identify effective therapies;\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-8\u0022\u003E\n               \u003Cp id=\u0022p-13\u0022\u003Ediscovery of epilepsy and drug toxicity genes;\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-9\u0022\u003E\n               \u003Cp id=\u0022p-14\u0022\u003Eautoimmune epilepsy, which lends itself, in some cases, to immune modulation therapy; and\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-10\u0022\u003E\n               \u003Cp id=\u0022p-15\u0022\u003Eneuroimaging, which has significantly impacted the ability to diagnose and treat the focus causing a seizure disorder.\u003C\/p\u003E\n            \u003C\/li\u003E\u003C\/ul\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EScientific Advances\u003C\/h2\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EDr Lowenstein also discussed some major scientific advances that, in time, may also significantly impact patient care in epilepsy, including\u003C\/p\u003E\n         \u003Cul class=\u0022list-unord \u0022 id=\u0022list-3\u0022\u003E\u003Cli id=\u0022list-item-11\u0022\u003E\n               \u003Cp id=\u0022p-17\u0022\u003Eoptogenetics as a novel way of treating epilepsy by modifying neuronal networks involved in seizures;\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-12\u0022\u003E\n               \u003Cp id=\u0022p-18\u0022\u003Ethe use of flexible arrays that conform to the brain\u2019s surface to investigate brain activity;\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-13\u0022\u003E\n               \u003Cp id=\u0022p-19\u0022\u003Einducible pluripotential stem cell use that might enable investigation of cells from patients with epilepsy who have defined gene mutations, ultimately facilitating identification of specific treatments; and\u003C\/p\u003E\n            \u003C\/li\u003E\u003Cli id=\u0022list-item-14\u0022\u003E\n               \u003Cp id=\u0022p-20\u0022\u003Ehigh throughput screening, a technique that has been used in zebrafish for screening of antiepileptic drug candidates.\u003C\/p\u003E\n            \u003C\/li\u003E\u003C\/ul\u003E\n         \u003Cp id=\u0022p-21\u0022\u003EDr Lowenstein highlighted 2 important large-scale projects involving patients with epilepsy. The Epilepsy Phenome\/Genome Project (EPGP) [The EPGP Collaborative. \u003Cem\u003EClin Trials\u003C\/em\u003E. 2013] began in 2006 and aimed to develop a database of detailed phenotype information for patients with specific forms of epilepsy; create a repository of DNA and cell lines on all project participants; assess the phenotypic characteristics of different cohorts for evidence of relationships between phenotype and genotype; and apply cutting edge technologies to the data collected.\u003C\/p\u003E\n         \u003Cp id=\u0022p-22\u0022\u003EThe largest cohort comprised patients with idiopathic generalized epilepsy with a first-degree relative who also had epilepsy, as well as patients with localization-related epilepsy with a first-degree relative with epilepsy. Another major cohort comprised patients with infantile spasms (IS), Lennox-Gastaut syndrome (LGS), or malformations of cortical development, and for whom both parents were triads.\u003C\/p\u003E\n         \u003Cp id=\u0022p-23\u0022\u003EThe Epi 4K collaborative [The Epi4K Consortium. \u003Cem\u003EEpilepsia\u003C\/em\u003E. 2012] involves a phenotyping and clinical informatics core and a sequencing, biostatistics, and bioinformatics core, both of which converge on 4 different projects that particularly focus on epileptic encephalopathies (EEs), multiplex families and pairs, prognosis, and copy number variant (CNV) detection.\u003C\/p\u003E\n         \u003Cp id=\u0022p-24\u0022\u003EDr Lowenstein discussed the EEs project from the Epi4K collaborative that comprised 2 main groups\u2014patients with either IS or LGS [Epi4K Consortium, Epilepsy Phenome\/Genome Project. \u003Cem\u003ENature\u003C\/em\u003E. 2013]. Most EEs do not show transgenerational transmission, and most families do not have sibling recurrence. Therefore, it was hypothesized that many patients with IS and LGS have \u003Cem\u003Ede novo\u003C\/em\u003E causative mutations that arise in the germline and are therefore inherited only in a particular individual. The group thus aimed to target families that would highlight the increased chance of finding \u003Cem\u003Ede novo\u003C\/em\u003E mutations. This required the availability of both biological parents to compare the genome of the proband with that of each parent. In addition, it was required that the parents did not have epilepsy and that there was no familial recurrence.\u003C\/p\u003E\n         \u003Cp id=\u0022p-25\u0022\u003EThis project showed that, in EEs, there is an overrepresentation of variants for mutations in genes that are intolerant, suggesting that they are causative.\u003C\/p\u003E\n         \u003Cp id=\u0022p-26\u0022\u003ENumerous other causative genes were also identified [Epi4K Consortium, Epilepsy Phenome\/Genome Project. \u003Cem\u003ENature\u003C\/em\u003E. 2013]. According to Dr Lowenstein, research to date has determined approximately 20% of the genetic basis of all EEs. Mutations in one of the causative genes, \u003Cem\u003EKCNT1\u003C\/em\u003E, are associated with a severe form of autosomal dominant frontal lobe epilepsy and another severe condition known as \u2018epilepsy of infancy with migrating focal seizures.\u2019 He shared the results of one study, demonstrating a significant increase in potassium channel current flow that correlated with disease severity associated with these gain-of-function mutations [Milligan CJ et al. \u003Cem\u003EAnn Neurol\u003C\/em\u003E. 2014]. That study also showed that exposure to quinidine can modify these currents by decreasing the mutation effect. Quinidine also had a variable effect on additional mutations that were studied, and the effect was somewhat correlated with disease severity.\u003C\/p\u003E\n         \u003Cp id=\u0022p-27\u0022\u003EThis research then led to the first attempt at targeted treatment using quinidine in a patient with \u003Cem\u003EKCNT1\u003C\/em\u003E mutation [Bearden D et al. \u003Cem\u003EAnn Neurol\u003C\/em\u003E. 2014]. Following administration of quinidine, improved psychomotor development and a marked reduction in seizure frequency was evident.\u003C\/p\u003E\n         \u003Cp id=\u0022p-28\u0022\u003EDr Lowenstein proposed that these findings constitute a proof-of-principle demonstration of the identification of a genetic basis of epilepsy, discovering a potential therapy for the specific mutation \u003Cem\u003Ein vitro\u003C\/em\u003E, and then introducing the treatment into a patient to ameliorate the disease. Importantly, it also provides answers to the first 2 of the universal patient questions, although the prognosis for such patients remains unknown. Nevertheless, these findings mark the beginning of a new era in epilepsy care, he concluded.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2015 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/15\/9\/4.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzlns1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}