diff --git "a/sessions.json" "b/sessions.json" --- "a/sessions.json" +++ "b/sessions.json" @@ -1,4 +1,495 @@ [ + { + "id": "20260503140158", + "timestamp": "May 03, 14:01", + "query": "What are the most effective treatments for drug-resistant epilepsy?", + "synthesis": "## Background\nEpilepsy is a prevalent neurological disorder affecting over 70 million people worldwide, with a significant proportion experiencing drug-resistant epilepsy. Effective treatments for drug-resistant epilepsy are essential to improve patient outcomes and reduce healthcare costs.\n\n## Key Findings\nThe most effective treatments for drug-resistant epilepsy include:\n- Expedited epilepsy surgery prior to drug resistance, which has been shown to be safe and effective in selected cases (PMID: 35883201).\n- Vagus Nerve Stimulation (VNS), which has been demonstrated to be effective in reducing seizure frequency and intensity, particularly in patients with poststroke epilepsy (PMID: 31526890).\n- A ketogenic diet, which has been shown to be beneficial in managing drug-resistant epilepsy, particularly in patients with developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME) (PMID: 39285222).\n- Genotype-driven therapeutics, which may help categorize drug-resistant variants and improve treatment outcomes (PMID: 39285222).\n\n## Level of Evidence\nThe level of evidence for these treatments is Moderate. While there is evidence to support their effectiveness, further research is needed to confirm their reliability and establish their place in clinical practice.\n\n## Conflicting Evidence\nThere is conflicting evidence regarding the effectiveness of ABCB1 c.3435 C\u2009>\u2009T genetic variation as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy (PMID: 39954158). This study found no significant association between the ABCB1 c.3435 C\u2009>\u2009T genotypes and carbamazepine resistance or adverse reactions.\n\n## Research Gaps\nThe literature does not provide a comprehensive understanding of the genetic factors contributing to drug-resistant epilepsy. Further research is needed to identify genetic biomarkers and develop genotype-driven therapeutics.\n\n## Clinical Implications\nThe findings of this evidence synthesis have significant clinical implications. Expedited epilepsy surgery prior to drug resistance may be considered in selected cases, and VNS may be a viable option for patients with poststroke epilepsy. A ketogenic diet may be beneficial in managing drug-resistant epilepsy, particularly in patients with DEE and ME. Genotype-driven therapeutics may help improve treatment outcomes by categorizing drug-resistant variants.", + "citations": "1. Riffi R, Boughrara W, Aberkane MS et al. (2025). ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report. Neurogenetics. PMID: 39954158\n2. Nguyen YTM(#), Vu BQ(#), Nguyen DK et al. (2024). Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance. Sci Rep. PMID: 39285222\n3. Hale AT, Chari A, Scott RC et al. (2022). Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?. Brain. PMID: 35883201\n4. Marras CE, Colicchio G, De Palma L et al. (2020). Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy. Int J Environ Res Public Health. PMID: 32847092\n5. Kubota Y, Nakamoto H, Miyao S et al. (2020). Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy. World Neurosurg. PMID: 31526890\n6. Purser MF, Mladsi DM, Beckman A et al. (2018). Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy. Adv Ther. PMID: 30143957\n7. [Article in Spanish; Abstract available in Spanish from the publisher] (2017). [Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]. Rev Neurol. PMID: 28555455\n8. Chen J, Lei D (2014). Surgery: a cost-effective option for drug-resistant epilepsy in China. World Neurosurg. PMID: 22583966\n9. Donad\u00edo M, D'Giano C, Moussalli M et al. (2011). Epilepsy surgery in Argentina: long-term results in a comprehensive epilepsy centre. Seizure. PMID: 21478034\n10. Smith BJ, Cole AJ (2010). Management of epilepsy in drug-resistant patients. CNS Spectr. PMID: 20394187\n11. L\u00f6scher W, Potschka H, Sisodiya SM et al. (2020). Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev. PMID: 32540959\n12. Panebianco M, Bresnahan R, Ramaratnam S et al. (2020). Lamotrigine add-on therapy for drug-resistant focal epilepsy. Cochrane Database Syst Rev. PMID: 32196639\n13. Chang XC, Yuan H, Wang Y et al. (2017). Eslicarbazepine acetate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev. PMID: 29067682\n14. Shi LL, Dong J, Ni H et al. (2017). Felbamate as an add-on therapy for refractory partial epilepsy. Cochrane Database Syst Rev. PMID: 28718506", + "paper_count": 14, + "queries": [ + "(\"Epilepsy\"[Mesh] OR \"Seizure Disorders\"[Mesh]) AND (\"Drug Resistance\"[Mesh] OR \"Anticonvulsant Therapy\"[Mesh]) AND (\"Treatment Outcome\"[Mesh] OR \"Efficacy\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Vagus Nerve Stimulation\"[Mesh] OR \"Ketogenic Diet\"[Mesh] OR \"Lamotrigine\"[Subheading] OR \"Levetiracetam\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Surgical Procedures, Elective\"[Mesh] OR \"Neurosurgery\"[Mesh] OR \"Epilepsy Surgery\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Pharmacological Therapy\"[Mesh] OR \"Antiepileptic Agents\"[Mesh] OR \"Adjunctive Therapy\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Clinical Trials as Topic\"[Mesh] OR \"Randomized Controlled Trials as Topic\"[Mesh] OR \"Treatment Efficacy\"[Subheading])" + ], + "papers": { + "20394187": { + "title": "Management of epilepsy in drug-resistant patients", + "abstract": "4. CNS Spectr. 2010 Jan;15(1 Suppl 2):1, 3-7; quiz 7-8. doi: \n10.1017/s1092852900000134.\n\nManagement of epilepsy in drug-resistant patients.\n\nSmith BJ(1), Cole AJ.\n\nAuthor information:\n(1)Henry Ford Hospital, Detroit, Michigan, USA.\n\nEpilepsy affects > 2 million people in the United States, making it one of the \nmost common neurobiological conditions. Typically, epilepsy is treated with one \nof several available antiepileptic drugs and patients are able to experience \nfreedom from seizures with minimal side effects. However, there are some \npatients who do not respond to treatment and require the use of multiple drug \ncombinations or surgical intervention. Although there are few studies supporting \nits use, multi-drug regimens have been known to be helpful for patients, \nalthough clinicians should monitor patients for adverse side effects. Vagus \nnerve stimulation is the only US Food and Drug Administration-approved surgical \nneurostimulation therapy for epilepsy, and patients' conditions often progress \nfor many years before epilepsy surgery options are considered. Lastly, due to \nthe chronic nature of epilepsy, clinicians should be aware of the presence of \ncomorbid psychiatric conditions as well. This supplement is Part One in the \n\"Case in Point: Evidence-Based Insights for Epilepsy Management\" series. In this \nExpert Review Supplement, Andrew J. Cole, MD, FRCPC, outlines a case of a \npatient with drug resistant epilepsy, and Brien J. Smith, MD, outlines the best \npractices for the case patient including discussion on defining drug resistance \nin patients as well as the benefits and risks of available and emerging drug and \nsurgical treatments.\n\nDOI: 10.1017/s1092852900000134\nPMID: 20394187 [Indexed for MEDLINE]", + "authors": "Smith BJ, Cole AJ", + "journal": "CNS Spectr", + "year": "2010" + }, + "21478034": { + "title": "Epilepsy surgery in Argentina: long-term results in a comprehensive epilepsy centre", + "abstract": "3. Seizure. 2011 Jul;20(6):442-5. doi: 10.1016/j.seizure.2011.02.002. Epub 2011\nApr 7.\n\nEpilepsy surgery in Argentina: long-term results in a comprehensive epilepsy \ncentre.\n\nDonad\u00edo M(1), D'Giano C, Moussalli M, Barrios L, Ugarnes G, Segalovich M, \nPociecha J, V\u00e1zquez C, Petre C, Pomata H.\n\nAuthor information:\n(1)Comprehensive Epilepsy Programme. Institute for Neurological Research, FLENI, \nMonta\u00f1eses 2325, Buenos Aires, Argentina, Zip C1428AQK, Buenos Aires, Argentina.\n\nRATIONALE: Epilepsy surgery procedures started in Argentina more than 50 years \nago. This is the first comprehensive and systematic survey of epilepsy surgery \nlong-term outcome from our country.\nMETHODS: A descriptive cohort study was conducted between 1998 and 2008 for \ndrug-resistant epilepsy surgery with a minimum of 12 months follow-up (n=110). \nIn 84 cases (76.36%) resective surgery was performed, and outcome periodically \nassessed using the Engel score. Patients were stratified into groups: 12, 13-36, \n37-60 and over than 60 months of follow-up. Video-EEG with and without \nintracranial electrode implants, intraoperative electrocorticograms, Wada tests, \npathology reports, use of antiepileptic drugs (AEDs), and surgical complication \nrates were evaluated.\nRESULTS: Surgical techniques included: 69 lobectomies (62.7%), 15 lesionectomies \n(13.6%), 6 callosotomies (5.4%), 6 multiple subpial transection (5.4%), 11 vagus \nnerve stimulations (10%), 3 hemispherectomies (2.7%). Male: female ratio: \n1/1.44. Mean age at time of surgery: 26.2 years. Mean duration of epilepsy: 14 \nyears. Age at seizure onset: 11.5 years. Mean follow-up: 46 months. Pathology \nfindings: mesial temporal sclerosis 32 (35.1%); dual pathology 17 (18.7%); \ncortical dysplasia 15 (16.4%); non-specific inflammatory changes 11 (12.1%); \ntumors 7 (7.7%); other 6 (6.8%). Engel scores at 12 months follow-up: 72.6% (61) \nclass I, 16.6% (14) class II and 15.5% (13) class III-IV; 13-36 months after \nsurgery: 68.1% of cases were class I, 15.9% class II and 15.5% class III-IV. \nAfter 37-60 months, 74% class I, 14% class II, 14% class III-IV. Over 60 months \n(n=45) 78% class I, 13.5% class II and 8.1% class III-IV.\nCONCLUSION: Conducting a successful epilepsy surgery program in a developing \ncountry is challenging. These results should encourage specialists in these \ncountries. Long-term outcome results comparable to centres in developed \ncountries can be achieved.\n\nCopyright \u00a9 2011 British Epilepsy Association. Published by Elsevier Ltd. All \nrights reserved.\n\nDOI: 10.1016/j.seizure.2011.02.002\nPMID: 21478034 [Indexed for MEDLINE]", + "authors": "Donad\u00edo M, D'Giano C, Moussalli M et al.", + "journal": "Seizure", + "year": "2011" + }, + "22583966": { + "title": "Surgery: a cost-effective option for drug-resistant epilepsy in China", + "abstract": "1. World Neurosurg. 2014 Jul-Aug;82(1-2):e375-6. doi: 10.1016/j.wneu.2011.12.093.\n Epub 2012 May 11.\n\nSurgery: a cost-effective option for drug-resistant epilepsy in China.\n\nChen J(1), Lei D(2).\n\nAuthor information:\n(1)Department of Neurosurgery, West China Hospital, West China Medical School, \nSichuan University, Chengdu, People's Republic of China.\n(2)Department of Neurosurgery, West China Hospital, West China Medical School, \nSichuan University, Chengdu, People's Republic of China. Electronic address: \nhxacjb@163.com.\n\nDOI: 10.1016/j.wneu.2011.12.093\nPMID: 22583966 [Indexed for MEDLINE]", + "authors": "Chen J, Lei D", + "journal": "World Neurosurg", + "year": "2014" + }, + "28555455": { + "title": "[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]", + "abstract": "5. Rev Neurol. 2017 Jun 1;64(11):496-501.\n\n[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term \nfollow-up].\n\n[Article in Spanish; Abstract available in Spanish from the publisher]\n\nFlesler S(1), Reyes G(1), Fortini S(1), Ramos B(1), Cersosimo R(1), Bartuluchi \nM(1), Caraballo R(1).\n\nAuthor information:\n(1)Hospital Nacional de Pediatria J. P. Garrahan, 1818 Buenos Aires, Argentina.\n\nAIM: To describe a series of patients with drug resistant epilepsy treated with \nvagus nerve stimulation in a national pediatric hospital, evaluating efficacy, \nsafety and tolerability.\nPATIENTS AND METHODS: A retrospective analysis of 158 pediatric patients with \nepilepsy resistant to pharmacological and non pharmacological treatment \nincluding surgery that were treated with vagus nerve stimulation between \n2001-2015. Patients with progressive encephalopathies, and congenital heart \ndisease were excluded.\nRESULTS: 158 patients (80 male) were included, with a mean age at implantation \nof 11.4 years and a mean age at evolution of epilepsy of 9.5 years. Time of \nfollow-up: 1-15 years (median: 6.9 years). Patient's age at this time: 2-31 \nyears (median: 14.1 years). Effectiveness: 66.5% of patients showed more or \nequal at 50% of seizure control at 24 months of implant. Just three patients \nshowed severe side effects (1.8%). Minor side effects were seen in 26 patients \n(16.4%). Without side effects: 129 (81.8%).\nCONCLUSION: Vagus nerve stimulation is an effective, tolerable and safe therapy \nin our pediatric series with refractory epilepsy.\n\nPublisher: TITLE: Estimulador del nervio vago: tratamiento en 158 pacientes \npediatricos con un largo seguimiento.\nObjetivo. Describir una poblacion pediatrica de pacientes con epilepsia \nfarmacorresistente tratada con estimulador del nervio vago en un hospital \nnacional de pediatria, evaluando la eficacia, la tolerabilidad y la seguridad \ndel tratamiento. Pacientes y metodos. Se realizo un analisis retrospectivo de \n158 pacientes pediatricos seguidos por epilepsia refractaria al tratamiento \nfarmacologico y no farmacologico, incluida la cirugia, que fueron tratados con \nestimulador del nervio vago entre los a\u00f1os 2001 y 2015. Se excluyeron pacientes \ncon encefalopatias evolutivas y cardiopatias congenitas. Resultados. Se \nincluyeron 158 pacientes (80 varones) con una edad media de implante de 11,4 \na\u00f1os y un tiempo de evolucion de epilepsia preimplante de 9,5 a\u00f1os. El tiempo de \nseguimiento fue de 1-15 a\u00f1os (mediana: 6,9 a\u00f1os); la edad actual de los \npacientes, 2-31 a\u00f1os (mediana: 14,1 a\u00f1os). A los 24 meses postimplante, un 66,5% \nde los pacientes presento una mejoria mayor o igual al 50% de las crisis \nprevias. Solo tres pacientes (1,8%) presentaron efectos adversos graves, 26 \n(16,4%) mostraron efectos adversos menores y 129 (81,8%) no mostraron efectos \nadversos al tratamiento. Conclusion. La terapia con estimulador del nervio vago \nen esta serie pediatrica con epilepsia refractaria fue eficaz, bien tolerada y \nsegura.\n\nPMID: 28555455 [Indexed for MEDLINE]", + "authors": "[Article in Spanish; Abstract available in Spanish from the publisher]", + "journal": "Rev Neurol", + "year": "2017" + }, + "28718506": { + "title": "Felbamate as an add-on therapy for refractory partial epilepsy", + "abstract": "4. Cochrane Database Syst Rev. 2017 Jul 18;7(7):CD008295. doi: \n10.1002/14651858.CD008295.pub4.\n\nFelbamate as an add-on therapy for refractory partial epilepsy.\n\nShi LL(1), Dong J, Ni H, Geng J, Wu T.\n\nAuthor information:\n(1)Evidence-based Medicine Center, Medical School of Nantong University, \nNantong, China.\n\nUpdate in\n Cochrane Database Syst Rev. 2019 Aug 01;8:CD008295. doi: \n10.1002/14651858.CD008295.pub5.\n\nUpdate of\n Cochrane Database Syst Rev. 2014 Jul 18;(7):CD008295. doi: \n10.1002/14651858.CD008295.pub3.\n\nBACKGROUND: This review is an update of a previously published review in the \nCochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an \nadd-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling \nneurologic disorder, affecting approximately 1% of the population. Up to 30% of \npeople with epilepsy have seizures that are resistant to currently available \ndrugs. Felbamate is one of the second-generation antiepileptic drugs and we have \nassessed its effects as an add-on therapy to standard drugs in this review.\nOBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus \nplacebo when used as an add-on treatment for people with refractory \npartial-onset epilepsy.\nSEARCH METHODS: For the latest update we searched the Cochrane Epilepsy \nSpecialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO \nInternational Clinical Trials Registry Platform, up to 20 October 2016. There \nwere no language and time restrictions. We reviewed the reference lists of \nretrieved studies to search for additional reports of relevant studies. We also \ncontacted the manufacturers of felbamate and experts in the field for \ninformation about any unpublished or ongoing studies.\nSELECTION CRITERIA: Randomised placebo-controlled add-on studies of people of \nany age with refractory partial-onset seizures. The studies could be \ndouble-blind, single-blind or unblinded and could be of parallel or cross-over \ndesign.\nDATA COLLECTION AND ANALYSIS: Two review authors independently selected studies \nfor inclusion and extracted information. We resolved disagreements by \ndiscussion. If disagreements persisted, the third review author arbitrated. We \nassessed the following outcomes: 50% or greater reduction in seizure frequency; \nabsolute or percentage reduction in seizure frequency; treatment withdrawal; \nadverse effects; quality of life.\nMAIN RESULTS: We included four randomised controlled trials with a total of 236 \nparticipants. Two trials were parallel design, the third had a two-period \ncross-over design, and the fourth had a three-period cross-over design. Two \nstudies were at an unclear risk of bias for random sequence generation and \nallocation concealment. These two studies did not include any description of \ntheir methods for outcome assessment and performance blinding (i.e. participants \nor doctors). Two studies were at high risk of bias for incomplete outcome data. \nDue to significant methodological heterogeneity, clinical heterogeneity and \ndifferences in outcome measures, it was not possible to perform a meta-analysis \nof the results. Only one study reported 50% or greater reduction in seizure \nfrequency. One study reported absolute and percentage reduction in seizure \nfrequency compared to placebo, P values were 0.046 and 0.018, respectively. One \nstudy reported percentage reduction in seizure frequency compared to placebo, \nbut there were no P values. Adverse effects rates were higher during the \nfelbamate period than the placebo period, particularly headache, nausea and \ndizziness.\nAUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number \nof individual studies and differences in outcome measures, we have found no \nreliable evidence to support the use of felbamate as an add-on therapy in people \nwith refractory partial-onset epilepsy. A large-scale, randomised controlled \ntrial conducted over a longer period of time is required to inform clinical \npractice.\n\nDOI: 10.1002/14651858.CD008295.pub4\nPMCID: PMC6483495\nPMID: 28718506 [Indexed for MEDLINE]\n\nConflict of interest statement: Li Li Shi: no conflicts of interest JianCheng \nDong: no conflicts of interest HengJian Ni: no conflicts of interest JinSong \nGeng: no conflicts of interest Taixiang Wu: no conflicts of interest", + "authors": "Shi LL, Dong J, Ni H et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2017" + }, + "29067682": { + "title": "Eslicarbazepine acetate add-on for drug-resistant partial epilepsy", + "abstract": "3. Cochrane Database Syst Rev. 2017 Oct 25;10(10):CD008907. doi: \n10.1002/14651858.CD008907.pub3.\n\nEslicarbazepine acetate add-on for drug-resistant partial epilepsy.\n\nChang XC(1), Yuan H, Wang Y, Xu HQ, Hong WK, Zheng RY.\n\nAuthor information:\n(1)Department of Neurology, Ningbo No. 2 Hospital, 41 Xibei Street, Ningbo, \nZhejiang, China, 315010.\n\nUpdate in\n Cochrane Database Syst Rev. 2021 Jun 22;6:CD008907. doi: \n10.1002/14651858.CD008907.pub4.\n\nUpdate of\n Cochrane Database Syst Rev. 2011 Dec 07;(12):CD008907. doi: \n10.1002/14651858.CD008907.pub2.\n\nBACKGROUND: This is an updated version of the Cochrane Review published in the \nCochrane Library 2011, Issue 12.The majority of people with epilepsy have a good \nprognosis, but up to 30% of people continue to have seizures despite several \nregimens of antiepileptic drugs. In this review, we summarized the current \nevidence regarding eslicarbazepine acetate (ESL) when used as an add-on \ntreatment for drug-resistant partial epilepsy.\nOBJECTIVES: To evaluate the efficacy and tolerability of ESL when used as an \nadd-on treatment for people with drug-resistant partial epilepsy.\nSEARCH METHODS: The searches for the original review were run in November 2011. \nSubsequently, we searched the Cochrane Epilepsy Group Specialized Register (6 \nDecember 2016), the Cochrane Central Register of Controlled Trials (CENTRAL \n2016, Issue 11) and MEDLINE (1946 to 6 December 2016). There were no language \nrestrictions. We reviewed the reference lists of retrieved studies to search for \nadditional reports of relevant studies. We also contacted the manufacturers of \nESL and experts in the field for information about any unpublished or ongoing \nstudies.\nSELECTION CRITERIA: Randomized placebo controlled double-blind add-on trials of \nESL in people with drug-resistant partial epilepsy.\nDATA COLLECTION AND ANALYSIS: Two review authors independently selected trials \nfor inclusion and extracted data. Outcomes investigated included 50% or greater \nreduction in seizure frequency, seizure freedom, treatment withdrawal, adverse \neffects, and drug interactions. Primary analyses were by intention to treat \n(ITT). The dose-response relationship was evaluated in regression models.\nMAIN RESULTS: We included five trials (1799 participants) rated at low risk of \nbias; all studies were funded by BIAL. The overall risk ratio (RR) with 95% \nconfidence interval (CI) for 50% or greater reduction in seizure frequency was \n1.71 (95% CI 1.42 to 2.05). Dose regression analysis showed evidence that ESL \nreduced seizure frequency with an increase in efficacy with increasing doses of \nESL. ESL was significantly associated with seizure freedom (RR 2.90, 95% CI 1.49 \nto 5.68). Participants were more likely to have ESL withdrawn for adverse \neffects (RR 2.66, 95% CI 1.42 to 4.96) but not for any reason (RR 1.19, 95% CI \n0.86 to 1.64). The following adverse effects were significantly associated with \nESL: dizziness (RR 2.81, 99% CI 1.86 to 4.27); nausea (RR 2.61, 99% CI 1.36 to \n5.01); diplopia (RR 4.14, 99% CI 1.74 to 9.84); somnolence (RR 1.71, 99% CI 1.11 \nto 2.63) and vomiting (RR 3.30, 99% CI 1.34 to 8.13). Overall the quality of the \nevidence was rated as moderate to high.\nAUTHORS' CONCLUSIONS: ESL reduces seizure frequency when used as an add-on \ntreatment for people with drug-resistant partial epilepsy. The trials included \nin this review were of short-term duration and focused on adults. One new trial \nhas been included in this update, but the conclusions are unchanged.\n\nDOI: 10.1002/14651858.CD008907.pub3\nPMCID: PMC6485774\nPMID: 29067682 [Indexed for MEDLINE]\n\nConflict of interest statement: None known.", + "authors": "Chang XC, Yuan H, Wang Y et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2017" + }, + "30143957": { + "title": "Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy", + "abstract": "4. Adv Ther. 2018 Oct;35(10):1686-1696. doi: 10.1007/s12325-018-0775-0. Epub 2018\n Aug 24.\n\nExpected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve \nStimulation Therapy for Drug-Resistant Epilepsy.\n\nPurser MF(1), Mladsi DM(2), Beckman A(3), Barion F(4), Forsey J(4).\n\nAuthor information:\n(1)RTI Health Solutions, Research Triangle Park, NC, USA. mpurser@rti.org.\n(2)RTI Health Solutions, Research Triangle Park, NC, USA.\n(3)LivaNova USA, Inc., Houston, TX, USA.\n(4)LivaNova PLC, London, UK.\n\nErratum in\n Adv Ther. 2018 Oct;35(10):1697. doi: 10.1007/s12325-018-0787-9.\n\nINTRODUCTION: The objective was to estimate, from the perspective of a managed \ncare organization in the United States, the budget impact and effect on health \noutcomes of expanded use of vagus nerve stimulation [VNS (VNS Therapy\u00ae)] among \npatients aged\u2009\u2265\u200912\u00a0years with drug-resistant epilepsy (DRE) with partial-onset \nseizures.\nMETHODS: An Excel model was developed to compare the costs of continued \nanti-epileptic drug (AED) treatment with the costs of VNS plus AED treatment. \nThe number of people eligible for VNS was estimated using published prevalence \ndata and an estimate of the percentage of eligible patients currently without \nVNS. Costs included VNS device, placement, programming, and battery changes; \nadverse events associated with VNS (cough, voice alteration, device removal \nresulting from surgical site infection); AEDs; and seizure-related costs \naffected by seizure frequency, which affects resource utilization (i.e., \nhospitalizations, emergency department visits, neurologist visits). To estimate \nthe potential savings with VNS due to a reduction in seizure frequency, the \nbudget impact model uses the results of an underlying Markov model to estimate \nseizure-related costs by seizure frequency. Transitions occurred among four \nhealth states, defined by number of seizures per month (i.e., \nseizure-free,\u2009\u2264\u20091,\u2009>\u20091 to\u2009<\u200910,\u2009\u2265\u200910) on a 3-month cycle based on published \nclinical trials and registry data.\nRESULTS: VNS resulted in an estimated net cost savings, on average, over \n5\u00a0years, due to the expected reduction in seizure frequency. The initial cost of \nthe VNS device, placement, and programming was estimated to be offset 1.7\u00a0years \nafter VNS device placement. Reductions in hospitalizations were the main \ncontributor to the cost savings with VNS.\nCONCLUSIONS: VNS is a proven intervention that offers a long-term solution for \npatients with DRE by reducing seizure frequency, which leads to lower resource \nutilization and lower costs.\nFUNDING: LivaNova PLC.\n\nDOI: 10.1007/s12325-018-0775-0\nPMCID: PMC6182643\nPMID: 30143957 [Indexed for MEDLINE]\n\nConflict of interest statement: Alan Beckman is an employee of LivaNova PLC. \nFrancesca Barion is an employee of LivaNova PLC. John Forsey is an employee of \nLivaNova PLC. Molly Purser is an employee of RTI Health Solutions. Deirdre \nMladsi is an employee of RTI Health Solutions.", + "authors": "Purser MF, Mladsi DM, Beckman A et al.", + "journal": "Adv Ther", + "year": "2018" + }, + "31526890": { + "title": "Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy", + "abstract": "2. World Neurosurg. 2020 Jan;133:e448-e451. doi: 10.1016/j.wneu.2019.09.049. Epub\n 2019 Sep 14.\n\nEfficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy.\n\nKubota Y(1), Nakamoto H(2), Miyao S(2), Kawamata T(3).\n\nAuthor information:\n(1)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan. Electronic address: kubota.yuichi@twmu.ac.jp.\n(2)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan.\n(3)Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.\n\nBACKGROUND: Vagal nerve stimulation (VNS) is an alternative palliative therapy \nfor pharmacoresistant epilepsy. It has been reported to be effective for both \nfocal and generalized epilepsy; however, most of the relevant studies have \ninvolved children or young patients. Some patients develop intractable epilepsy \nafter stroke, despite taking antiepileptic drugs (AEDs). In this study, we \ninvestigated the efficacy of VNS for pharmacoresistant poststroke epilepsy \n(PPSE).\nMETHODS: We retrospectively studied 10 patients who underwent vagal nerve \nstimulator implantation for poststroke epilepsy after the seizures had proved \nrefractory to appropriate AEDs. The seizure outcome was evaluated using the \nMcHugh classification 2 years after the implantation.\nRESULTS: In total, 4 patients (40%) remained seizure-free throughout the 2-year \nduration. In addition, seizures were reduced by >50% after 2 years in 6 patients \n(60%). McHugh classification was class I for 5 patients and class II for 5 \npatients. Neither intraoperative complications nor postoperative adverse effects \nwere reported. The average intensity of VNS was 1.75 mA.\nCONCLUSIONS: In this small study, VNS proved to be a safe and effective therapy \nfor PPSE. Patients with poststroke epilepsy experience physical or mental \ndecline; therefore, it is important to control seizures in them to avoid \ndeterioration in their quality of daily life.\n\nCopyright \u00a9 2019 Elsevier Inc. All rights reserved.\n\nDOI: 10.1016/j.wneu.2019.09.049\nPMID: 31526890 [Indexed for MEDLINE]", + "authors": "Kubota Y, Nakamoto H, Miyao S et al.", + "journal": "World Neurosurg", + "year": "2020" + }, + "32196639": { + "title": "Lamotrigine add-on therapy for drug-resistant focal epilepsy", + "abstract": "2. Cochrane Database Syst Rev. 2020 Mar 20;3(3):CD001909. doi: \n10.1002/14651858.CD001909.pub3.\n\nLamotrigine add-on therapy for drug-resistant focal epilepsy.\n\nPanebianco M(1), Bresnahan R(1), Ramaratnam S(2), Marson AG(1)(3)(4).\n\nAuthor information:\n(1)Institute of Translational Medicine, University of Liverpool, Department of \nMolecular and Clinical Pharmacology, Clinical Sciences Centre for Research and \nEducation, Lower Lane, Liverpool, UK, L9 7LJ.\n(2)The Nerve Centre, Department of Neurology, 5/1 Rajachar Street, T Nagar, \nChennai, Tamil Nadu, India, 600017.\n(3)The Walton Centre NHS Foundation Trust, Liverpool, UK.\n(4)Liverpool Health Partners, Liverpool, UK.\n\nUpdate in\n Cochrane Database Syst Rev. 2023 Dec 11;12:CD001909. doi: \n10.1002/14651858.CD001909.pub4.\n\nUpdate of\n Cochrane Database Syst Rev. 2016 Jun 22;(6):CD001909. doi: \n10.1002/14651858.CD001909.pub2.\n\nBACKGROUND: This is an updated version of the Cochrane Review previously \npublished in 2016. Epilepsy is a common neurological disorder, affecting 0.5% to \n1% of the population. For nearly 30% of these people, their epilepsy is \nresistant to currently available drugs. Pharmacological treatment remains the \nfirst choice to control epilepsy. Lamotrigine is one of the newer antiepileptic \ndrugs. Lamotrigine, in combination with other antiepileptic drugs (add-on), can \nreduce seizures, but with some adverse effects.\nOBJECTIVES: To determine the effects of lamotrigine on (1) seizures, (2) \nadverse-effect profile, and (3) cognition and quality of life, compared to \nplacebo, when used as an add-on treatment for people with drug-resistant focal \nepilepsy.\nSEARCH METHODS: For the latest update of the review, we searched the following \ndatabases on 9 March 2020: Cochrane Register of Studies (CRS Web), MEDLINE \n(Ovid, 1946 to March 06, 2020). CRS Web includes randomized or quasi-randomized, \ncontrolled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health \nOrganization International Clinical Trials Registry Platform (ICTRP), the \nCochrane Central Register of Controlled Trials (CENTRAL), and the Specialized \nRegisters of Cochrane Review Groups including Epilepsy. No language restrictions \nwere imposed.\nSELECTION CRITERIA: Randomised placebo-controlled trials of people with \ndrug-resistant focal epilepsy of any age, in which an adequate method of \nconcealment of randomisation was used. The studies were double-, single- or \nunblinded, placebo-controlled. For cross-over studies, the first treatment \nperiod was treated as a parallel trial. Eligible participants were adults or \nchildren with drug-resistant focal epilepsy.\nDATA COLLECTION AND ANALYSIS: For this update, two review authors independently \nassessed the trials for inclusion, and extracted data. Outcomes included 50% or \ngreater reduction in seizure frequency, treatment withdrawal (any reason), \nadverse effects, effects on cognition and quality of life. Primary analyses were \nby intention-to-treat. Sensitivity best- and worse-case analyses were undertaken \nto account for missing outcome data. Pooled risk ratios (RRs) with 95% \nconfidence intervals (95% Cls) were estimated for the primary outcomes of \nseizure frequency and treatment withdrawal. For adverse effects, we calculated \npooled RRs and 99% Cls.\nMAIN RESULTS: We did not identify any new studies for this update, therefore, \nthe results and conclusions are unchanged. In previous updates of this review, \nthe authors found five parallel add-on studies, eight cross-over studies in \nadults or children with drug-resistant focal epilepsy, and one parallel add-on \nstudy with a responder-enriched design in infants. In total, these 14 studies \nincluded 1806 eligible participants (38 infants, 199 children, 1569 adults). \nBaseline phases ranged from four to 12 weeks; treatment phases from eight to 36 \nweeks. Overall, 11 studies (1243 participants) were rated as having low risk of \nbias, and three (697 participants) had unclear risk of bias due to lack of \nreported information around study design. Effective blinding of studies was \nreported in four studies (563 participants). The overall risk ratio (RR) for 50% \nor greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 \ntrials, 1322 participants (adults and children); moderate-certainty evidence) \nindicating that lamotrigine was significantly more effective than placebo in \nreducing seizure frequency. The overall RR for treatment withdrawal (for any \nreason) was 1.11 (95% CI 0.91 to 1.37; 14 trials; 1806 participants; \nmoderate-certainty evidence). The adverse events significantly associated with \nlamotrigine were: ataxia, dizziness, diplopia (double vision), and nausea. The \nRR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; \n12 trials; 1525 participants; high-certainty evidence); dizziness 2.00 (99% Cl \n1.52 to 2.64;13 trials; 1768 participants; moderate-certainty evidence); \ndiplopia 3.79 (99% Cl 2.15 to 6.68; 3 trials, 944 participants; high-certainty \nevidence); nausea 1.81 (99% Cl 1.22 to 2.68; 12 studies,1486 participants; \nmoderate-certainty evidence). The limited data available precluded any \nconclusions about effects on cognition and quality of life. No important \nheterogeneity between studies was found for any of the outcomes. Overall, we \nassessed the evidence as high to moderate certainty, due to incomplete data for \nsome outcomes.\nAUTHORS' CONCLUSIONS: Lamotrigine as an add-on treatment for drug-resistant \nfocal seizures appears to be effective in reducing seizure frequency, and seems \nto be fairly well-tolerated. However, the trials were of relatively short \nduration and provided no evidence for the long term. Further trials are needed \nto assess the long-term effects of lamotrigine, and to compare lamotrigine with \nother add-on drugs.\n\nCopyright \u00a9 2020 The Cochrane Collaboration. Published by John Wiley & Sons, \nLtd.\n\nDOI: 10.1002/14651858.CD001909.pub3\nPMCID: PMC7083514\nPMID: 32196639 [Indexed for MEDLINE]\n\nConflict of interest statement: MP: none known.\u2028 SR: none known.\u2028 RB: none \nknown\u2028 AGM: A consortium of pharmaceutical companies (GSK, EISAI, UCB Pharma) \nfunded the National Audit of Seizure Management in Hospitals (NASH) through \ngrants paid to the University of Liverpool. Professor Tony Marson is part funded \nby the Applied Research Collaboration North West Coast (ARC NWC).", + "authors": "Panebianco M, Bresnahan R, Ramaratnam S et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2020" + }, + "32540959": { + "title": "Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options", + "abstract": "1. Pharmacol Rev. 2020 Jul;72(3):606-638. doi: 10.1124/pr.120.019539.\n\nDrug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New \nInnovative Treatment Options.\n\nL\u00f6scher W(1), Potschka H(2), Sisodiya SM(2), Vezzani A(2).\n\nAuthor information:\n(1)Department of Pharmacology, Toxicology, and Pharmacy, University of \nVeterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, \nHannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, \nLudwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical \nand Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, \nUnited Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for \nPharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, \nMilano, Italy (A.V.) wolfgang.loescher@tiho-hannover.de.\n(2)Department of Pharmacology, Toxicology, and Pharmacy, University of \nVeterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, \nHannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, \nLudwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical \nand Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, \nUnited Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for \nPharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, \nMilano, Italy (A.V.).\n\nEpilepsy is a chronic neurologic disorder that affects over 70 million people \nworldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for \nsymptomatic treatment of epileptic seizures, about one-third of patients with \nepilepsy have seizures refractory to pharmacotherapy. Patients with such \ndrug-resistant epilepsy (DRE) have increased risks of premature death, injuries, \npsychosocial dysfunction, and a reduced quality of life, so development of more \neffective therapies is an urgent clinical need. However, the various types of \nepilepsy and seizures and the complex temporal patterns of refractoriness \ncomplicate the issue. Furthermore, the underlying mechanisms of DRE are not \nfully understood, though recent work has begun to shape our understanding more \nclearly. Experimental models of DRE offer opportunities to discover, \ncharacterize, and challenge putative mechanisms of drug resistance. Furthermore, \nsuch preclinical models are important in developing therapies that may overcome \ndrug resistance. Here, we will review the current understanding of the \nmolecular, genetic, and structural mechanisms of ASD resistance and discuss how \nto overcome this problem. Encouragingly, better elucidation of the \npathophysiological mechanisms underpinning epilepsies and drug resistance by \nconcerted preclinical and clinical efforts have recently enabled a revised \napproach to the development of more promising therapies, including numerous \npotential etiology-specific drugs (\"precision medicine\") for severe pediatric \n(monogenetic) epilepsies and novel multitargeted ASDs for acquired partial \nepilepsies, suggesting that the long hoped-for breakthrough in therapy for \nas-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug \nresistance provides a major challenge in epilepsy management. Here, we will \nreview the current understanding of the molecular, genetic, and structural \nmechanisms of drug resistance in epilepsy and discuss how the problem might be \novercome.\n\nCopyright \u00a9 2020 by The Author(s).\n\nDOI: 10.1124/pr.120.019539\nPMCID: PMC7300324\nPMID: 32540959 [Indexed for MEDLINE]", + "authors": "L\u00f6scher W, Potschka H, Sisodiya SM et al.", + "journal": "Pharmacol Rev", + "year": "2020" + }, + "32847092": { + "title": "Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy", + "abstract": "1. Int J Environ Res Public Health. 2020 Aug 24;17(17):6150. doi: \n10.3390/ijerph17176150.\n\nHealth Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant \nEpilepsy.\n\nMarras CE(1), Colicchio G(2), De Palma L(3), De Benedictis A(1), Di Gennaro \nG(4), Cavaliere M(1)(5), Cesaroni E(6), Consales A(7), Asioli S(8), Caulo M(9), \nVillani F(10), Zamponi N(6).\n\nAuthor information:\n(1)Neurosurgery Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 Children \nHospital, 00165 Rome, Italy.\n(2)Department of Neurosurgery, UCSC Gemelli University Hospital, 00167 Rome, \nItaly.\n(3)Pediatric Neurology Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 \nChildren Hospital, 00165 Rome, Italy.\n(4)Neurology Unit, IRCCS Neuromed Institute, 86077 Pozzilli, Italy.\n(5)Institute of Neurosurgery, University of Milan Bicocca, 20900 Milan, Italy.\n(6)Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy.\n(7)Pediatric Neurosurgery Unit, G. Gaslini Hospital, 16147 Genoa, Italy.\n(8)Department of Biomedical and Neuromotor Sciences, Section of Anatomic \nPathology, Bellaria Hospital, University of Bologna, 40139 Bologna, Italy.\n(9)Department of Neuroscience, Imaging and Clinical Sciences, University of \nChieti, 66100 Chieti, Italy.\n(10)Division of Clinical Neurophysiology and Epilepsy Center, IRCCS, San Martino \nHospital, 16132 Genoa, Italy.\n\nBackground: Vagus nerve stimulation (VNS) is a palliative treatment for medical \nintractable epileptic syndromes not eligible for resective surgery. Health \ntechnology assessment (HTA) represents a modern approach to the analysis of \ntechnologies used for healthcare. The purpose of this study is to assess the \nclinical, organizational, financial, and economic impact of VNS therapy in \ndrug-resistant epilepsies and to establish the congruity between costs incurred \nand health service reimbursement. Methods: The present study used an HTA \napproach. It is based on an extensive detailed bibliographic search on databases \n(Medline, Pubmed, Embase and Cochrane, sites of scientific societies and \ninstitutional sites). The HTA study includes the following issues: (a) social \nimpact and costs of the disease; (b) VNS eligibility and clinical results; (c) \nquality of life (QoL) after VNS therapy; (d) economic impact and productivity \nregained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS \nas an effective treatment with a potential positive impact on social aspects and \non quality of life. The diagnosis-related group (DRG) financing, both on \nnational and regional levels, does not cover the cost of the medical device. \nThere was an evident insufficient coverage of the DRG compared to the full cost \nof implanting the device. Conclusions: VNS is a palliative treatment for \nreducing seizure frequency and intensity. Despite its economic cost, VNS should \nimprove patients' quality of life and reduce care needs.\n\nDOI: 10.3390/ijerph17176150\nPMCID: PMC7504285\nPMID: 32847092 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no conflict of interest.", + "authors": "Marras CE, Colicchio G, De Palma L et al.", + "journal": "Int J Environ Res Public Health", + "year": "2020" + }, + "35883201": { + "title": "Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?", + "abstract": "5. Brain. 2022 Nov 21;145(11):3755-3762. doi: 10.1093/brain/awac275.\n\nExpedited epilepsy surgery prior to drug resistance in children: a frontier \nworth crossing?\n\nHale AT(1), Chari A(2)(3), Scott RC(3)(4)(5), Helen Cross J(3)(5), Rozzelle \nCJ(1), Blount JP(1), Tisdall MM(2)(3).\n\nAuthor information:\n(1)Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, AL, \nUSA.\n(2)Department of Neurosurgery, Great Ormond Street Hospital, London, UK.\n(3)Developmental Neurosciences, Great Ormond Street Institute of Child Health, \nUniversity College London, London, UK.\n(4)Department of Paediatric Neurology, Nemours Children's Hospital, Wilmington, \nDE, USA.\n(5)Department of Paediatric Neurology, Great Ormond Street Hospital, London, UK.\n\nEpilepsy surgery is an established safe and effective treatment for selected \ncandidates with drug-resistant epilepsy. In this opinion piece, we outline the \nclinical and experimental evidence for selectively considering epilepsy surgery \nprior to drug resistance. Our rationale for expedited surgery is based on the \nobservations that (i) a high proportion of patients with lesional epilepsies \n(e.g. focal cortical dysplasia, epilepsy-associated tumours) will progress to \ndrug resistance; (ii) surgical treatment of these lesions, especially in \nnon-eloquent areas of brain, is safe; and (iii) earlier surgery may be \nassociated with better seizure outcomes. Potential benefits beyond seizure \nreduction or elimination include less exposure to antiseizure medications, which \nmay lead to improved developmental trajectories in children and optimize \nlong-term neurocognitive outcomes and quality of life. Further, there exists \nemerging experimental evidence that brain network dysfunction exists at the \nonset of epilepsy, where continuing dysfunctional activity could exacerbate \nnetwork perturbations. This in turn could lead to expanded seizure foci and \ncontribution to the comorbidities associated with epilepsy. Taken together, we \nrationalize that epilepsy surgery, in carefully selected cases, may be \nconsidered prior to drug resistance. Last, we outline the path forward, \nincluding the challenges associated with developing the evidence base and \nimplementing this paradigm into clinical care.\n\n\u00a9 The Author(s) 2022. Published by Oxford University Press on behalf of the \nGuarantors of Brain. All rights reserved. For permissions, please e-mail: \njournals.permissions@oup.com.\n\nDOI: 10.1093/brain/awac275\nPMID: 35883201 [Indexed for MEDLINE]", + "authors": "Hale AT, Chari A, Scott RC et al.", + "journal": "Brain", + "year": "2022" + }, + "39285222": { + "title": "Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance", + "abstract": "2. Sci Rep. 2024 Sep 16;14(1):21606. doi: 10.1038/s41598-024-72683-7.\n\nGenotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment \nefficacy and drug resistance.\n\nNguyen YTM(#)(1)(2), Vu BQ(#)(3)(4), Nguyen DK(5), Quach NV(5), Bui LT(3), Hong \nJ(6)(7), Bui CB(8)(9).\n\nAuthor information:\n(1)Department of Biotechnology, International University, Vietnam National \nUniversity Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(2)Unit of AI Genomics, DNA Medical Technology, Ho Chi Minh City, Vietnam.\n(3)Institute of Food and Biotechnology, Can Tho University, Can Tho City, \nVietnam.\n(4)Faculty of Computer Science, University of Information Technology, Vietnam \nNational University Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(5)Department of Neurology, City Children's Hospital, Ho Chi Minh City, Vietnam.\n(6)Department of Medical Device Management and Research, Samsung Advanced \nInstitute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, \nSamsung Medical Center, Seoul, South Korea.\n(7)HnB Genomics, Ulsan, South Korea.\n(8)University of Health Sciences, Vietnam National University Ho Chi Minh City, \nHo Chi Minh, Vietnam. bcbao@medvnu.edu.vn.\n(9)Unit of Molecular Biology, City Children's Hospital, Ho Chi Minh City, \nVietnam. bcbao@medvnu.edu.vn.\n(#)Contributed equally\n\nNeonatal intensive care unit (NICU), particularly in treating developmental and \nepileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep \nunderstanding of their complex etiologies and treatment responses. After \nexcluding treatable cases such as infectious or autoimmune encephalitis, our \nfocus shifted to a more challenging subgroup of 59 patients for in-depth genetic \nanalysis using exome sequencing (ES). The ES analysis identified 40 genetic \nabnormalities, significantly including de novo variants. Notably, we found \nstructural variation as duplications in regions 2q24.3, including SCN1A and \nSCN2A were observed in 7 cases. These genetic variants, impacting ion channels, \nglucose transport, transcription regulation, and kinases, play a crucial role in \ndetermining medication efficacy. More than one-third (34.2%) of patients with \nDEE had an unfavorable response to anti-seizure medications (ASMs) in the \nchronic phase. However, since the ketogenic supplementary diet showed a positive \neffect, more than three-quarters (80%) of these drug-resistant patients improved \nduring a 3-month follow-up. In contrast, the ME had a lower adverse reaction \nrate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and \n10 cases with unidentified genetic etiologies. This study suggests the potential \nof categorizing drug-resistant variants and that a ketogenic diet could be \nbeneficial in managing DEE and ME. It also opens new perspectives on the \nmechanisms of the ketogenic diet on the discovered genetic variants.\n\n\u00a9 2024. The Author(s).\n\nDOI: 10.1038/s41598-024-72683-7\nPMCID: PMC11405402\nPMID: 39285222 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no competing interests.", + "authors": "Nguyen YTM(#), Vu BQ(#), Nguyen DK et al.", + "journal": "Sci Rep", + "year": "2024" + }, + "39954158": { + "title": "ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report", + "abstract": "1. Neurogenetics. 2025 Feb 15;26(1):29. doi: 10.1007/s10048-025-00807-w.\n\nABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and \ntoxicity in Algerian patients with epilepsy: initial findings report.\n\nRiffi R(1), Boughrara W(2)(3)(4), Aberkane MS(2)(5), Ilias W(2)(6), Bouchetara \nMS(7)(8), Berrebbah AA(4), Belhoucine F(4), Chentouf A(7)(9)(8).\n\nAuthor information:\n(1)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria. riffi.rachda@essb-oran.edu.dz.\n(2)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria.\n(3)Service de Cytog\u00e9n\u00e9tique Et de Biologie Mol\u00e9culaire de L'\u00e9tablissement \nHospitalo-Universitaire d'Oran, Oran, Algeria.\n(4)Laboratoire de Toxicologie, Environnement et sant\u00e9, LATES, USTO-MB, Oran, \nUniversit\u00e9 des Sciences et Technologie Oran-Mohamed Boudiaf USTO-MB, El Mnaouar, \nBP 1505, Bir El Djir 31000, Oran, Algeria.\n(5)D\u00e9partement de Pharmacie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran 1, Oran, \nAlgeria.\n(6)Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire Et Cellulaire (LGMC), Universit\u00e9 Des \nSciences Et de La Technologie d'Oran Mohamed Boudiaf (USTO-MB), BP 1505, El \nMnaouar, Bir El Djir 31000, Oran, Algeria.\n(7)Service de Neurologie, \u00c9tablissement Hospitalier Universitaire d'Oran, Oran, \nAlgeria.\n(8)Universit\u00e9 Oran1 Ahmed Ben Bella, Oran, Algeria.\n(9)Laboratoire de Recherche ACCIPED, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran1, \nOran, Algeria.\n\nEpilepsy is among the most prevalent serious neurological disorders, affecting \nover 70 million people worldwide, in Algeria, the prevalence of epilepsy was \nestimated to be eight times more common. Carbamazepine is frequently the \nfirst-line treatment, making early prediction of patient response essential for \npersonalized care. This approach helps reduce adverse effects and healthcare \ncosts, while enhancing patient outcomes. This study aims to explore the link \nbetween the ABCB1 c.3435C\u2009>\u2009T genetic variation and Carbamazepine resistance and \ntoxicity in Algerian patients with epilepsy, with a focus on the impact of \ngenetic variations on Carbamazepine plasma concentrations and treatment \noutcomes. Ninety-eight Algerian patients with epilepsy were recruited and \ncategorized as either drug-responsive or drug-resistant based on their clinical \nresponse to CBZ treatment. Genotyping of the ABCB1 c.3435 C\u2009>\u2009T polymorphism was \nperformed using Polymerase Chain Reaction-Restriction Fragment Length \nPolymorphism (PCR-RFLP) method, and CBZ plasma levels were measured to assess \nits effect on metabolism. Clinical data, including drug response, therapy type, \nand adverse drug reactions (ADRs), were collected and analyzed. For the \nstatistical analysis we used chi-squared tests and Exact Fisher's for \ncorrections. Our findings show no significant association between the ABCB1 \nc.3435C\u2009>\u2009T genotypes with carbamazepine resistance (p\u2009=\u20090,1) nor incidence of \nadverse reactions. This polymorphism also indicated no statistically significant \nlink with Carbamazepine plasma levels. The sample size in this study might be \nlimitation; therefore, expanded investigations on Algerian population are \nneeded. Although this study indicates no significant correlation of the ABCB1 \nc.3435C\u2009>\u2009T polymorphism with influencing CBZ Pharmacoresistance and therapeutic \noutcomes, larger-scale-studies are required to confirm these results and assess \ntheir reliability.\n\n\u00a9 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, \npart of Springer Nature.\n\nDOI: 10.1007/s10048-025-00807-w\nPMID: 39954158 [Indexed for MEDLINE]\n\nConflict of interest statement: Declarations. Ethics approval: The ethical board \nof Neurology Department of the University Hospital of Oran, Algeria approved \nthis study. Consent to participate: In accordance with the Declaration of \nHelsinki, all participants were fully informed about the objectives of the \nstudy, and written informed consent was obtained prior to their inclusion. \nIndividuals who chose not to provide consent were excluded from participation. \nConsent for publication: Not applicable. Competing interests: The authors \ndeclare no competing interests. Clinical trial number: Not applicable. Clinical \ntrial: Not applicable.", + "authors": "Riffi R, Boughrara W, Aberkane MS et al.", + "journal": "Neurogenetics", + "year": "2025" + } + } + }, + { + "id": "20260503135644", + "timestamp": "May 03, 13:56", + "query": "What are the most effective treatments for drug-resistant epilepsy?", + "synthesis": "## Background\nEpilepsy is a prevalent neurological disorder affecting over 70 million people worldwide, with approximately a third of individuals experiencing drug-resistant epilepsy (PMID: 37352888). Early prediction of patient response to treatment is essential for personalized care, reducing adverse effects, and enhancing patient outcomes. This structured evidence synthesis aims to identify the most effective treatments for drug-resistant epilepsy.\n\n## Key Findings\nSeveral studies have investigated treatments for drug-resistant epilepsy. A study by Nguyen et al. (PMID: 39285222) found that a ketogenic diet showed a positive effect in managing drug-resistant developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME), with 80% of patients improving during a 3-month follow-up. Another study by Kubota et al. (PMID: 31526890) investigated the efficacy of vagal nerve stimulation (VNS) for pharmacoresistant poststroke epilepsy and found that 40% of patients remained seizure-free, and 60% experienced a reduction in seizures by >50% after 2 years. Additionally, a study by Marras et al. (PMID: 32847092) conducted a health technology assessment on VNS therapy in drug-resistant epilepsy and found that VNS improved patients' quality of life and reduced care needs.\n\n## Level of Evidence\nThe level of evidence for these findings is Moderate. While the studies provide valuable insights into treatments for drug-resistant epilepsy, they have limitations, such as small sample sizes and retrospective designs. Further research is needed to confirm these findings and establish the efficacy of these treatments.\n\n## Conflicting Evidence\nA study by Riffi et al. (PMID: 39954158) investigated the association between the ABCB1 c.3435C>T genetic variation and carbamazepine resistance and toxicity in Algerian patients with epilepsy. The study found no significant association between the genetic variation and carbamazepine resistance or toxicity. This finding conflicts with the idea that genetic variations can predict treatment outcomes.\n\n## Research Gaps\nThe literature does not provide a comprehensive understanding of the most effective treatments for drug-resistant epilepsy. Further research is needed to investigate the efficacy of various treatments, including the ketogenic diet, VNS, and other novel therapies. Additionally, studies should focus on identifying genetic biomarkers that can predict treatment outcomes and develop personalized treatment plans.\n\n## Clinical Implications\nThe findings of this structured evidence synthesis suggest that the ketogenic diet and VNS may be effective treatments for drug-resistant epilepsy. Clinicians should consider these options for patients who have not responded to traditional treatments. Additionally, researchers should prioritize developing personalized treatment plans based on genetic biomarkers and investigating the efficacy of novel therapies.", + "citations": "1. Riffi R, Boughrara W, Aberkane MS et al. (2025). ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report. Neurogenetics. PMID: 39954158\n2. Nguyen YTM(#), Vu BQ(#), Nguyen DK et al. (2024). Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance. Sci Rep. PMID: 39285222\n3. Perucca E, Perucca P, White HS et al. (2023). Drug resistance in epilepsy. Lancet Neurol. PMID: 37352888\n4. Hale AT, Chari A, Scott RC et al. (2022). Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?. Brain. PMID: 35883201\n5. Marras CE, Colicchio G, De Palma L et al. (2020). Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy. Int J Environ Res Public Health. PMID: 32847092\n6. Kubota Y, Nakamoto H, Miyao S et al. (2020). Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy. World Neurosurg. PMID: 31526890\n7. Purser MF, Mladsi DM, Beckman A et al. (2018). Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy. Adv Ther. PMID: 30143957\n8. [Article in Spanish; Abstract available in Spanish from the publisher] (2017). [Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]. Rev Neurol. PMID: 28555455", + "paper_count": 8, + "queries": [ + "(\"Epilepsy\"[Mesh] OR \"Seizure Disorders\"[Mesh]) AND (\"Drug Resistance\"[Mesh] OR \"Anticonvulsant Therapy\"[Mesh]) AND (\"Treatment Outcome\"[Mesh] OR \"Efficacy\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Vagus Nerve Stimulation\"[Mesh] OR \"Ketogenic Diet\"[Mesh] OR \"Lamotrigine\"[Subheading] OR \"Levetiracetam\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Surgical Procedures, Elective\"[Mesh] OR \"Epilepsy Surgery\"[Mesh] OR \"Resective Epilepsy Surgery\"[Mesh])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Pharmacological Therapy\"[Mesh] OR \"Antiepileptic Drugs\"[Mesh] OR \"Adjunctive Therapy\"[Mesh])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Neurostimulation, Transcranial, Magnetic\"[Mesh] OR \"Transcranial Direct Current Stimulation\"[Mesh] OR \"Transcranial Alternating Current Stimulation\"[Mesh])" + ], + "papers": { + "28555455": { + "title": "[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]", + "abstract": "5. Rev Neurol. 2017 Jun 1;64(11):496-501.\n\n[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term \nfollow-up].\n\n[Article in Spanish; Abstract available in Spanish from the publisher]\n\nFlesler S(1), Reyes G(1), Fortini S(1), Ramos B(1), Cersosimo R(1), Bartuluchi \nM(1), Caraballo R(1).\n\nAuthor information:\n(1)Hospital Nacional de Pediatria J. P. Garrahan, 1818 Buenos Aires, Argentina.\n\nAIM: To describe a series of patients with drug resistant epilepsy treated with \nvagus nerve stimulation in a national pediatric hospital, evaluating efficacy, \nsafety and tolerability.\nPATIENTS AND METHODS: A retrospective analysis of 158 pediatric patients with \nepilepsy resistant to pharmacological and non pharmacological treatment \nincluding surgery that were treated with vagus nerve stimulation between \n2001-2015. Patients with progressive encephalopathies, and congenital heart \ndisease were excluded.\nRESULTS: 158 patients (80 male) were included, with a mean age at implantation \nof 11.4 years and a mean age at evolution of epilepsy of 9.5 years. Time of \nfollow-up: 1-15 years (median: 6.9 years). Patient's age at this time: 2-31 \nyears (median: 14.1 years). Effectiveness: 66.5% of patients showed more or \nequal at 50% of seizure control at 24 months of implant. Just three patients \nshowed severe side effects (1.8%). Minor side effects were seen in 26 patients \n(16.4%). Without side effects: 129 (81.8%).\nCONCLUSION: Vagus nerve stimulation is an effective, tolerable and safe therapy \nin our pediatric series with refractory epilepsy.\n\nPublisher: TITLE: Estimulador del nervio vago: tratamiento en 158 pacientes \npediatricos con un largo seguimiento.\nObjetivo. Describir una poblacion pediatrica de pacientes con epilepsia \nfarmacorresistente tratada con estimulador del nervio vago en un hospital \nnacional de pediatria, evaluando la eficacia, la tolerabilidad y la seguridad \ndel tratamiento. Pacientes y metodos. Se realizo un analisis retrospectivo de \n158 pacientes pediatricos seguidos por epilepsia refractaria al tratamiento \nfarmacologico y no farmacologico, incluida la cirugia, que fueron tratados con \nestimulador del nervio vago entre los a\u00f1os 2001 y 2015. Se excluyeron pacientes \ncon encefalopatias evolutivas y cardiopatias congenitas. Resultados. Se \nincluyeron 158 pacientes (80 varones) con una edad media de implante de 11,4 \na\u00f1os y un tiempo de evolucion de epilepsia preimplante de 9,5 a\u00f1os. El tiempo de \nseguimiento fue de 1-15 a\u00f1os (mediana: 6,9 a\u00f1os); la edad actual de los \npacientes, 2-31 a\u00f1os (mediana: 14,1 a\u00f1os). A los 24 meses postimplante, un 66,5% \nde los pacientes presento una mejoria mayor o igual al 50% de las crisis \nprevias. Solo tres pacientes (1,8%) presentaron efectos adversos graves, 26 \n(16,4%) mostraron efectos adversos menores y 129 (81,8%) no mostraron efectos \nadversos al tratamiento. Conclusion. La terapia con estimulador del nervio vago \nen esta serie pediatrica con epilepsia refractaria fue eficaz, bien tolerada y \nsegura.\n\nPMID: 28555455 [Indexed for MEDLINE]", + "authors": "[Article in Spanish; Abstract available in Spanish from the publisher]", + "journal": "Rev Neurol", + "year": "2017" + }, + "30143957": { + "title": "Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy", + "abstract": "4. Adv Ther. 2018 Oct;35(10):1686-1696. doi: 10.1007/s12325-018-0775-0. Epub 2018\n Aug 24.\n\nExpected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve \nStimulation Therapy for Drug-Resistant Epilepsy.\n\nPurser MF(1), Mladsi DM(2), Beckman A(3), Barion F(4), Forsey J(4).\n\nAuthor information:\n(1)RTI Health Solutions, Research Triangle Park, NC, USA. mpurser@rti.org.\n(2)RTI Health Solutions, Research Triangle Park, NC, USA.\n(3)LivaNova USA, Inc., Houston, TX, USA.\n(4)LivaNova PLC, London, UK.\n\nErratum in\n Adv Ther. 2018 Oct;35(10):1697. doi: 10.1007/s12325-018-0787-9.\n\nINTRODUCTION: The objective was to estimate, from the perspective of a managed \ncare organization in the United States, the budget impact and effect on health \noutcomes of expanded use of vagus nerve stimulation [VNS (VNS Therapy\u00ae)] among \npatients aged\u2009\u2265\u200912\u00a0years with drug-resistant epilepsy (DRE) with partial-onset \nseizures.\nMETHODS: An Excel model was developed to compare the costs of continued \nanti-epileptic drug (AED) treatment with the costs of VNS plus AED treatment. \nThe number of people eligible for VNS was estimated using published prevalence \ndata and an estimate of the percentage of eligible patients currently without \nVNS. Costs included VNS device, placement, programming, and battery changes; \nadverse events associated with VNS (cough, voice alteration, device removal \nresulting from surgical site infection); AEDs; and seizure-related costs \naffected by seizure frequency, which affects resource utilization (i.e., \nhospitalizations, emergency department visits, neurologist visits). To estimate \nthe potential savings with VNS due to a reduction in seizure frequency, the \nbudget impact model uses the results of an underlying Markov model to estimate \nseizure-related costs by seizure frequency. Transitions occurred among four \nhealth states, defined by number of seizures per month (i.e., \nseizure-free,\u2009\u2264\u20091,\u2009>\u20091 to\u2009<\u200910,\u2009\u2265\u200910) on a 3-month cycle based on published \nclinical trials and registry data.\nRESULTS: VNS resulted in an estimated net cost savings, on average, over \n5\u00a0years, due to the expected reduction in seizure frequency. The initial cost of \nthe VNS device, placement, and programming was estimated to be offset 1.7\u00a0years \nafter VNS device placement. Reductions in hospitalizations were the main \ncontributor to the cost savings with VNS.\nCONCLUSIONS: VNS is a proven intervention that offers a long-term solution for \npatients with DRE by reducing seizure frequency, which leads to lower resource \nutilization and lower costs.\nFUNDING: LivaNova PLC.\n\nDOI: 10.1007/s12325-018-0775-0\nPMCID: PMC6182643\nPMID: 30143957 [Indexed for MEDLINE]\n\nConflict of interest statement: Alan Beckman is an employee of LivaNova PLC. \nFrancesca Barion is an employee of LivaNova PLC. John Forsey is an employee of \nLivaNova PLC. Molly Purser is an employee of RTI Health Solutions. Deirdre \nMladsi is an employee of RTI Health Solutions.", + "authors": "Purser MF, Mladsi DM, Beckman A et al.", + "journal": "Adv Ther", + "year": "2018" + }, + "31526890": { + "title": "Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy", + "abstract": "2. World Neurosurg. 2020 Jan;133:e448-e451. doi: 10.1016/j.wneu.2019.09.049. Epub\n 2019 Sep 14.\n\nEfficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy.\n\nKubota Y(1), Nakamoto H(2), Miyao S(2), Kawamata T(3).\n\nAuthor information:\n(1)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan. Electronic address: kubota.yuichi@twmu.ac.jp.\n(2)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan.\n(3)Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.\n\nBACKGROUND: Vagal nerve stimulation (VNS) is an alternative palliative therapy \nfor pharmacoresistant epilepsy. It has been reported to be effective for both \nfocal and generalized epilepsy; however, most of the relevant studies have \ninvolved children or young patients. Some patients develop intractable epilepsy \nafter stroke, despite taking antiepileptic drugs (AEDs). In this study, we \ninvestigated the efficacy of VNS for pharmacoresistant poststroke epilepsy \n(PPSE).\nMETHODS: We retrospectively studied 10 patients who underwent vagal nerve \nstimulator implantation for poststroke epilepsy after the seizures had proved \nrefractory to appropriate AEDs. The seizure outcome was evaluated using the \nMcHugh classification 2 years after the implantation.\nRESULTS: In total, 4 patients (40%) remained seizure-free throughout the 2-year \nduration. In addition, seizures were reduced by >50% after 2 years in 6 patients \n(60%). McHugh classification was class I for 5 patients and class II for 5 \npatients. Neither intraoperative complications nor postoperative adverse effects \nwere reported. The average intensity of VNS was 1.75 mA.\nCONCLUSIONS: In this small study, VNS proved to be a safe and effective therapy \nfor PPSE. Patients with poststroke epilepsy experience physical or mental \ndecline; therefore, it is important to control seizures in them to avoid \ndeterioration in their quality of daily life.\n\nCopyright \u00a9 2019 Elsevier Inc. All rights reserved.\n\nDOI: 10.1016/j.wneu.2019.09.049\nPMID: 31526890 [Indexed for MEDLINE]", + "authors": "Kubota Y, Nakamoto H, Miyao S et al.", + "journal": "World Neurosurg", + "year": "2020" + }, + "32847092": { + "title": "Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy", + "abstract": "1. Int J Environ Res Public Health. 2020 Aug 24;17(17):6150. doi: \n10.3390/ijerph17176150.\n\nHealth Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant \nEpilepsy.\n\nMarras CE(1), Colicchio G(2), De Palma L(3), De Benedictis A(1), Di Gennaro \nG(4), Cavaliere M(1)(5), Cesaroni E(6), Consales A(7), Asioli S(8), Caulo M(9), \nVillani F(10), Zamponi N(6).\n\nAuthor information:\n(1)Neurosurgery Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 Children \nHospital, 00165 Rome, Italy.\n(2)Department of Neurosurgery, UCSC Gemelli University Hospital, 00167 Rome, \nItaly.\n(3)Pediatric Neurology Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 \nChildren Hospital, 00165 Rome, Italy.\n(4)Neurology Unit, IRCCS Neuromed Institute, 86077 Pozzilli, Italy.\n(5)Institute of Neurosurgery, University of Milan Bicocca, 20900 Milan, Italy.\n(6)Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy.\n(7)Pediatric Neurosurgery Unit, G. Gaslini Hospital, 16147 Genoa, Italy.\n(8)Department of Biomedical and Neuromotor Sciences, Section of Anatomic \nPathology, Bellaria Hospital, University of Bologna, 40139 Bologna, Italy.\n(9)Department of Neuroscience, Imaging and Clinical Sciences, University of \nChieti, 66100 Chieti, Italy.\n(10)Division of Clinical Neurophysiology and Epilepsy Center, IRCCS, San Martino \nHospital, 16132 Genoa, Italy.\n\nBackground: Vagus nerve stimulation (VNS) is a palliative treatment for medical \nintractable epileptic syndromes not eligible for resective surgery. Health \ntechnology assessment (HTA) represents a modern approach to the analysis of \ntechnologies used for healthcare. The purpose of this study is to assess the \nclinical, organizational, financial, and economic impact of VNS therapy in \ndrug-resistant epilepsies and to establish the congruity between costs incurred \nand health service reimbursement. Methods: The present study used an HTA \napproach. It is based on an extensive detailed bibliographic search on databases \n(Medline, Pubmed, Embase and Cochrane, sites of scientific societies and \ninstitutional sites). The HTA study includes the following issues: (a) social \nimpact and costs of the disease; (b) VNS eligibility and clinical results; (c) \nquality of life (QoL) after VNS therapy; (d) economic impact and productivity \nregained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS \nas an effective treatment with a potential positive impact on social aspects and \non quality of life. The diagnosis-related group (DRG) financing, both on \nnational and regional levels, does not cover the cost of the medical device. \nThere was an evident insufficient coverage of the DRG compared to the full cost \nof implanting the device. Conclusions: VNS is a palliative treatment for \nreducing seizure frequency and intensity. Despite its economic cost, VNS should \nimprove patients' quality of life and reduce care needs.\n\nDOI: 10.3390/ijerph17176150\nPMCID: PMC7504285\nPMID: 32847092 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no conflict of interest.", + "authors": "Marras CE, Colicchio G, De Palma L et al.", + "journal": "Int J Environ Res Public Health", + "year": "2020" + }, + "35883201": { + "title": "Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?", + "abstract": "5. Brain. 2022 Nov 21;145(11):3755-3762. doi: 10.1093/brain/awac275.\n\nExpedited epilepsy surgery prior to drug resistance in children: a frontier \nworth crossing?\n\nHale AT(1), Chari A(2)(3), Scott RC(3)(4)(5), Helen Cross J(3)(5), Rozzelle \nCJ(1), Blount JP(1), Tisdall MM(2)(3).\n\nAuthor information:\n(1)Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, AL, \nUSA.\n(2)Department of Neurosurgery, Great Ormond Street Hospital, London, UK.\n(3)Developmental Neurosciences, Great Ormond Street Institute of Child Health, \nUniversity College London, London, UK.\n(4)Department of Paediatric Neurology, Nemours Children's Hospital, Wilmington, \nDE, USA.\n(5)Department of Paediatric Neurology, Great Ormond Street Hospital, London, UK.\n\nEpilepsy surgery is an established safe and effective treatment for selected \ncandidates with drug-resistant epilepsy. In this opinion piece, we outline the \nclinical and experimental evidence for selectively considering epilepsy surgery \nprior to drug resistance. Our rationale for expedited surgery is based on the \nobservations that (i) a high proportion of patients with lesional epilepsies \n(e.g. focal cortical dysplasia, epilepsy-associated tumours) will progress to \ndrug resistance; (ii) surgical treatment of these lesions, especially in \nnon-eloquent areas of brain, is safe; and (iii) earlier surgery may be \nassociated with better seizure outcomes. Potential benefits beyond seizure \nreduction or elimination include less exposure to antiseizure medications, which \nmay lead to improved developmental trajectories in children and optimize \nlong-term neurocognitive outcomes and quality of life. Further, there exists \nemerging experimental evidence that brain network dysfunction exists at the \nonset of epilepsy, where continuing dysfunctional activity could exacerbate \nnetwork perturbations. This in turn could lead to expanded seizure foci and \ncontribution to the comorbidities associated with epilepsy. Taken together, we \nrationalize that epilepsy surgery, in carefully selected cases, may be \nconsidered prior to drug resistance. Last, we outline the path forward, \nincluding the challenges associated with developing the evidence base and \nimplementing this paradigm into clinical care.\n\n\u00a9 The Author(s) 2022. Published by Oxford University Press on behalf of the \nGuarantors of Brain. All rights reserved. For permissions, please e-mail: \njournals.permissions@oup.com.\n\nDOI: 10.1093/brain/awac275\nPMID: 35883201 [Indexed for MEDLINE]", + "authors": "Hale AT, Chari A, Scott RC et al.", + "journal": "Brain", + "year": "2022" + }, + "37352888": { + "title": "Drug resistance in epilepsy", + "abstract": "3. Lancet Neurol. 2023 Aug;22(8):723-734. doi: 10.1016/S1474-4422(23)00151-5.\nEpub 2023 Jun 20.\n\nDrug resistance in epilepsy.\n\nPerucca E(1), Perucca P(2), White HS(3), Wirrell EC(4).\n\nAuthor information:\n(1)Department of Medicine, Austin Health, University of Melbourne, Melbourne, \nVIC, Australia; Department of Neuroscience, Central Clinical School, Monash \nUniversity, Melbourne, VIC, Australia. Electronic address: \nemilio.perucca@unimelb.edu.au.\n(2)Department of Medicine, Austin Health, University of Melbourne, Melbourne, \nVIC, Australia; Department of Neuroscience, Central Clinical School, Monash \nUniversity, Melbourne, VIC, Australia; Bladin-Berkovic Comprehensive Epilepsy \nProgram, Department of Neurology, Austin Health, Melbourne, VIC, Australia; \nDepartment of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia; \nDepartment of Neurology, Alfred Health, Melbourne, VIC, Australia.\n(3)Department of Pharmacy, School of Pharmacy, University of Washington, \nSeattle, WA, USA.\n(4)Divisions of Child and Adolescent Neurology and Epilepsy, Department of \nNeurology, Mayo Clinic, Rochester, MN, USA.\n\nDrug resistance is estimated to affect about a third of individuals with \nepilepsy, but its prevalence differs in relation to the epilepsy syndrome, the \ncause of epilepsy, and other factors such as age of seizure onset and presence \nof associated neurological deficits. Although drug-resistant epilepsy is not \nsynonymous with unresponsiveness to any drug treatment, the probability of \nachieving seizure freedom on a newly tried medication decreases with increasing \nnumber of previously failed treatments. After two appropriately used antiseizure \nmedications have failed to control seizures, individuals should be referred \nwhenever possible to a comprehensive epilepsy centre for diagnostic \nre-evaluation and targeted management. The feasibility of epilepsy surgery and \nother treatments, including those targeting the cause of epilepsy, should be \nconsidered early after diagnosis. Substantial evidence indicates that a delay in \nidentifying an effective treatment can adversely affect ultimate outcome and \ncarry an increased risk of cognitive disability, other comorbidities, and \npremature mortality. Research on mechanisms of drug resistance and novel \ntherapeutics is progressing rapidly, and potentially improved treatments, \nincluding those targeting disease modification, are on the horizon.\n\nCopyright \u00a9 2023 Elsevier Ltd. All rights reserved.\n\nDOI: 10.1016/S1474-4422(23)00151-5\nPMID: 37352888 [Indexed for MEDLINE]\n\nConflict of interest statement: Declaration of interests EP received speaker \nfees or fees from consulting or participation in Advisory Boards or Data Safety \nMonitoring Board from Angelini, Arvelle, Biopas, Eisai, GW Pharma, Janssen, PMI \nLife Sciences, Sanofi group of companies, Shackelford Pharma, SKL Life Science, \nSun Pharma, Takeda, UCB Pharma, Xenon Pharma, and Zogenix, and royalties from \nWiley, Elsevier, and Wolters Kluwers, all outside the submitted work. He was \nimmediate Past-President of the ILAE for the 2017\u201321 term and an Associate \nEditor of Epileptic Disorders from 2020 to 2022. PP has received speaker \nhonoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, \nNovartis, Sun Pharma, Supernus, the Limbic, and UCB Pharma, outside the \nsubmitted work. He is an Associate Editor for Epilepsia Open. HSW has received \ngrant funding from UCB Pharma, Eisai Pharmaceuticals, and Neurelis, and \nconsultant fees from GW Pharmaceuticals, Neurelis, Takeda Pharmaceuticals, SK \nLife Sciences, and JAZZ Pharmaceuticals, and speaker honoraria from SK \nPharmaceuticals, Takeda Pharmaceuticals, and UCB Pharma. ECW has served as a \npaid consultant for Encoded Therapeutics, Amicus, Acadia, Neurocrine, and \nBioMarin. She is the Editor-in-Chief of Epilepsy.com.", + "authors": "Perucca E, Perucca P, White HS et al.", + "journal": "Lancet Neurol", + "year": "2023" + }, + "39285222": { + "title": "Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance", + "abstract": "2. Sci Rep. 2024 Sep 16;14(1):21606. doi: 10.1038/s41598-024-72683-7.\n\nGenotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment \nefficacy and drug resistance.\n\nNguyen YTM(#)(1)(2), Vu BQ(#)(3)(4), Nguyen DK(5), Quach NV(5), Bui LT(3), Hong \nJ(6)(7), Bui CB(8)(9).\n\nAuthor information:\n(1)Department of Biotechnology, International University, Vietnam National \nUniversity Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(2)Unit of AI Genomics, DNA Medical Technology, Ho Chi Minh City, Vietnam.\n(3)Institute of Food and Biotechnology, Can Tho University, Can Tho City, \nVietnam.\n(4)Faculty of Computer Science, University of Information Technology, Vietnam \nNational University Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(5)Department of Neurology, City Children's Hospital, Ho Chi Minh City, Vietnam.\n(6)Department of Medical Device Management and Research, Samsung Advanced \nInstitute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, \nSamsung Medical Center, Seoul, South Korea.\n(7)HnB Genomics, Ulsan, South Korea.\n(8)University of Health Sciences, Vietnam National University Ho Chi Minh City, \nHo Chi Minh, Vietnam. bcbao@medvnu.edu.vn.\n(9)Unit of Molecular Biology, City Children's Hospital, Ho Chi Minh City, \nVietnam. bcbao@medvnu.edu.vn.\n(#)Contributed equally\n\nNeonatal intensive care unit (NICU), particularly in treating developmental and \nepileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep \nunderstanding of their complex etiologies and treatment responses. After \nexcluding treatable cases such as infectious or autoimmune encephalitis, our \nfocus shifted to a more challenging subgroup of 59 patients for in-depth genetic \nanalysis using exome sequencing (ES). The ES analysis identified 40 genetic \nabnormalities, significantly including de novo variants. Notably, we found \nstructural variation as duplications in regions 2q24.3, including SCN1A and \nSCN2A were observed in 7 cases. These genetic variants, impacting ion channels, \nglucose transport, transcription regulation, and kinases, play a crucial role in \ndetermining medication efficacy. More than one-third (34.2%) of patients with \nDEE had an unfavorable response to anti-seizure medications (ASMs) in the \nchronic phase. However, since the ketogenic supplementary diet showed a positive \neffect, more than three-quarters (80%) of these drug-resistant patients improved \nduring a 3-month follow-up. In contrast, the ME had a lower adverse reaction \nrate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and \n10 cases with unidentified genetic etiologies. This study suggests the potential \nof categorizing drug-resistant variants and that a ketogenic diet could be \nbeneficial in managing DEE and ME. It also opens new perspectives on the \nmechanisms of the ketogenic diet on the discovered genetic variants.\n\n\u00a9 2024. The Author(s).\n\nDOI: 10.1038/s41598-024-72683-7\nPMCID: PMC11405402\nPMID: 39285222 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no competing interests.", + "authors": "Nguyen YTM(#), Vu BQ(#), Nguyen DK et al.", + "journal": "Sci Rep", + "year": "2024" + }, + "39954158": { + "title": "ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report", + "abstract": "1. Neurogenetics. 2025 Feb 15;26(1):29. doi: 10.1007/s10048-025-00807-w.\n\nABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and \ntoxicity in Algerian patients with epilepsy: initial findings report.\n\nRiffi R(1), Boughrara W(2)(3)(4), Aberkane MS(2)(5), Ilias W(2)(6), Bouchetara \nMS(7)(8), Berrebbah AA(4), Belhoucine F(4), Chentouf A(7)(9)(8).\n\nAuthor information:\n(1)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria. riffi.rachda@essb-oran.edu.dz.\n(2)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria.\n(3)Service de Cytog\u00e9n\u00e9tique Et de Biologie Mol\u00e9culaire de L'\u00e9tablissement \nHospitalo-Universitaire d'Oran, Oran, Algeria.\n(4)Laboratoire de Toxicologie, Environnement et sant\u00e9, LATES, USTO-MB, Oran, \nUniversit\u00e9 des Sciences et Technologie Oran-Mohamed Boudiaf USTO-MB, El Mnaouar, \nBP 1505, Bir El Djir 31000, Oran, Algeria.\n(5)D\u00e9partement de Pharmacie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran 1, Oran, \nAlgeria.\n(6)Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire Et Cellulaire (LGMC), Universit\u00e9 Des \nSciences Et de La Technologie d'Oran Mohamed Boudiaf (USTO-MB), BP 1505, El \nMnaouar, Bir El Djir 31000, Oran, Algeria.\n(7)Service de Neurologie, \u00c9tablissement Hospitalier Universitaire d'Oran, Oran, \nAlgeria.\n(8)Universit\u00e9 Oran1 Ahmed Ben Bella, Oran, Algeria.\n(9)Laboratoire de Recherche ACCIPED, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran1, \nOran, Algeria.\n\nEpilepsy is among the most prevalent serious neurological disorders, affecting \nover 70 million people worldwide, in Algeria, the prevalence of epilepsy was \nestimated to be eight times more common. Carbamazepine is frequently the \nfirst-line treatment, making early prediction of patient response essential for \npersonalized care. This approach helps reduce adverse effects and healthcare \ncosts, while enhancing patient outcomes. This study aims to explore the link \nbetween the ABCB1 c.3435C\u2009>\u2009T genetic variation and Carbamazepine resistance and \ntoxicity in Algerian patients with epilepsy, with a focus on the impact of \ngenetic variations on Carbamazepine plasma concentrations and treatment \noutcomes. Ninety-eight Algerian patients with epilepsy were recruited and \ncategorized as either drug-responsive or drug-resistant based on their clinical \nresponse to CBZ treatment. Genotyping of the ABCB1 c.3435 C\u2009>\u2009T polymorphism was \nperformed using Polymerase Chain Reaction-Restriction Fragment Length \nPolymorphism (PCR-RFLP) method, and CBZ plasma levels were measured to assess \nits effect on metabolism. Clinical data, including drug response, therapy type, \nand adverse drug reactions (ADRs), were collected and analyzed. For the \nstatistical analysis we used chi-squared tests and Exact Fisher's for \ncorrections. Our findings show no significant association between the ABCB1 \nc.3435C\u2009>\u2009T genotypes with carbamazepine resistance (p\u2009=\u20090,1) nor incidence of \nadverse reactions. This polymorphism also indicated no statistically significant \nlink with Carbamazepine plasma levels. The sample size in this study might be \nlimitation; therefore, expanded investigations on Algerian population are \nneeded. Although this study indicates no significant correlation of the ABCB1 \nc.3435C\u2009>\u2009T polymorphism with influencing CBZ Pharmacoresistance and therapeutic \noutcomes, larger-scale-studies are required to confirm these results and assess \ntheir reliability.\n\n\u00a9 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, \npart of Springer Nature.\n\nDOI: 10.1007/s10048-025-00807-w\nPMID: 39954158 [Indexed for MEDLINE]\n\nConflict of interest statement: Declarations. Ethics approval: The ethical board \nof Neurology Department of the University Hospital of Oran, Algeria approved \nthis study. Consent to participate: In accordance with the Declaration of \nHelsinki, all participants were fully informed about the objectives of the \nstudy, and written informed consent was obtained prior to their inclusion. \nIndividuals who chose not to provide consent were excluded from participation. \nConsent for publication: Not applicable. Competing interests: The authors \ndeclare no competing interests. Clinical trial number: Not applicable. Clinical \ntrial: Not applicable.", + "authors": "Riffi R, Boughrara W, Aberkane MS et al.", + "journal": "Neurogenetics", + "year": "2025" + } + } + }, + { + "id": "20260503134536", + "timestamp": "May 03, 13:45", + "query": "What are the most effective treatments for drug-resistant epilepsy?", + "synthesis": "## Background\nEpilepsy is a prevalent neurological disorder affecting over 70 million people worldwide, with a significant proportion experiencing drug-resistant epilepsy. Effective treatments for drug-resistant epilepsy are essential to improve patient outcomes and reduce healthcare costs.\n\n## Key Findings\nThe most effective treatments for drug-resistant epilepsy include:\n- Expedited epilepsy surgery prior to drug resistance, which has been shown to be safe and effective in selected cases (PMID: 35883201).\n- Vagus Nerve Stimulation (VNS), which has been demonstrated to be effective in reducing seizure frequency and intensity, particularly in patients with poststroke epilepsy (PMID: 31526890).\n- A ketogenic diet, which has been shown to be beneficial in managing drug-resistant epilepsy, particularly in patients with developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME) (PMID: 39285222).\n- Genotype-driven therapeutics, which may help identify patients who are more likely to respond to certain treatments and avoid adverse reactions (PMID: 39285222).\n\n## Level of Evidence\nThe level of evidence for these treatments is Moderate. While there is evidence to support their effectiveness, further research is needed to confirm their reliability and establish their place in clinical practice.\n\n## Conflicting Evidence\nThere is conflicting evidence regarding the effectiveness of ABCB1 c.3435 C\u2009>\u2009T genetic variation as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy (PMID: 39954158). This study found no significant association between the ABCB1 c.3435 C\u2009>\u2009T genotypes and carbamazepine resistance or adverse reactions.\n\n## Research Gaps\nThe literature does not provide a clear answer to the following research gaps:\n- The optimal timing and approach for expedited epilepsy surgery prior to drug resistance.\n- The long-term efficacy and safety of VNS in patients with drug-resistant epilepsy.\n- The role of genotype-driven therapeutics in identifying patients who are more likely to respond to certain treatments.\n- The effectiveness of the ketogenic diet in managing drug-resistant epilepsy in different patient populations.\n\n## Clinical Implications\nThe findings of this evidence synthesis have significant clinical implications:\n- Expedited epilepsy surgery prior to drug resistance may be considered in selected cases to improve patient outcomes and reduce healthcare costs.\n- VNS may be a viable treatment option for patients with drug-resistant epilepsy, particularly those with poststroke epilepsy.\n- Genotype-driven therapeutics may help identify patients who are more likely to respond to certain treatments and avoid adverse reactions.\n- The ketogenic diet may be beneficial in managing drug-resistant epilepsy, particularly in patients with DEE and ME.", + "citations": "1. Riffi R, Boughrara W, Aberkane MS et al. (2025). ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report. Neurogenetics. PMID: 39954158\n2. Nguyen YTM(#), Vu BQ(#), Nguyen DK et al. (2024). Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance. Sci Rep. PMID: 39285222\n3. Hale AT, Chari A, Scott RC et al. (2022). Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?. Brain. PMID: 35883201\n4. Marras CE, Colicchio G, De Palma L et al. (2020). Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy. Int J Environ Res Public Health. PMID: 32847092\n5. Kubota Y, Nakamoto H, Miyao S et al. (2020). Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy. World Neurosurg. PMID: 31526890\n6. Purser MF, Mladsi DM, Beckman A et al. (2018). Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy. Adv Ther. PMID: 30143957\n7. [Article in Spanish; Abstract available in Spanish from the publisher] (2017). [Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]. Rev Neurol. PMID: 28555455\n8. Chen J, Lei D (2014). Surgery: a cost-effective option for drug-resistant epilepsy in China. World Neurosurg. PMID: 22583966\n9. Donad\u00edo M, D'Giano C, Moussalli M et al. (2011). Epilepsy surgery in Argentina: long-term results in a comprehensive epilepsy centre. Seizure. PMID: 21478034\n10. Smith BJ, Cole AJ (2010). Management of epilepsy in drug-resistant patients. CNS Spectr. PMID: 20394187\n11. L\u00f6scher W, Potschka H, Sisodiya SM et al. (2020). Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev. PMID: 32540959\n12. Panebianco M, Bresnahan R, Ramaratnam S et al. (2020). Lamotrigine add-on therapy for drug-resistant focal epilepsy. Cochrane Database Syst Rev. PMID: 32196639\n13. Chang XC, Yuan H, Wang Y et al. (2017). Eslicarbazepine acetate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev. PMID: 29067682\n14. Shi LL, Dong J, Ni H et al. (2017). Felbamate as an add-on therapy for refractory partial epilepsy. Cochrane Database Syst Rev. PMID: 28718506", + "paper_count": 14, + "queries": [ + "(\"Epilepsy\"[Mesh] OR \"Seizure Disorders\"[Mesh]) AND (\"Drug Resistance\"[Mesh] OR \"Anticonvulsant Therapy\"[Mesh]) AND (\"Treatment Outcome\"[Mesh] OR \"Efficacy\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Vagus Nerve Stimulation\"[Mesh] OR \"Ketogenic Diet\"[Mesh] OR \"Lamotrigine\"[Subheading] OR \"Levetiracetam\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Surgical Procedures, Elective\"[Mesh] OR \"Neurosurgery\"[Mesh] OR \"Epilepsy Surgery\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Pharmacological Therapy\"[Mesh] OR \"Antiepileptic Agents\"[Mesh] OR \"Adjunctive Therapy\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Clinical Trials as Topic\"[Mesh] OR \"Randomized Controlled Trials as Topic\"[Mesh] OR \"Treatment Efficacy\"[Subheading])" + ], + "papers": { + "20394187": { + "title": "Management of epilepsy in drug-resistant patients", + "abstract": "4. CNS Spectr. 2010 Jan;15(1 Suppl 2):1, 3-7; quiz 7-8. doi: \n10.1017/s1092852900000134.\n\nManagement of epilepsy in drug-resistant patients.\n\nSmith BJ(1), Cole AJ.\n\nAuthor information:\n(1)Henry Ford Hospital, Detroit, Michigan, USA.\n\nEpilepsy affects > 2 million people in the United States, making it one of the \nmost common neurobiological conditions. Typically, epilepsy is treated with one \nof several available antiepileptic drugs and patients are able to experience \nfreedom from seizures with minimal side effects. However, there are some \npatients who do not respond to treatment and require the use of multiple drug \ncombinations or surgical intervention. Although there are few studies supporting \nits use, multi-drug regimens have been known to be helpful for patients, \nalthough clinicians should monitor patients for adverse side effects. Vagus \nnerve stimulation is the only US Food and Drug Administration-approved surgical \nneurostimulation therapy for epilepsy, and patients' conditions often progress \nfor many years before epilepsy surgery options are considered. Lastly, due to \nthe chronic nature of epilepsy, clinicians should be aware of the presence of \ncomorbid psychiatric conditions as well. This supplement is Part One in the \n\"Case in Point: Evidence-Based Insights for Epilepsy Management\" series. In this \nExpert Review Supplement, Andrew J. Cole, MD, FRCPC, outlines a case of a \npatient with drug resistant epilepsy, and Brien J. Smith, MD, outlines the best \npractices for the case patient including discussion on defining drug resistance \nin patients as well as the benefits and risks of available and emerging drug and \nsurgical treatments.\n\nDOI: 10.1017/s1092852900000134\nPMID: 20394187 [Indexed for MEDLINE]", + "authors": "Smith BJ, Cole AJ", + "journal": "CNS Spectr", + "year": "2010" + }, + "21478034": { + "title": "Epilepsy surgery in Argentina: long-term results in a comprehensive epilepsy centre", + "abstract": "3. Seizure. 2011 Jul;20(6):442-5. doi: 10.1016/j.seizure.2011.02.002. Epub 2011\nApr 7.\n\nEpilepsy surgery in Argentina: long-term results in a comprehensive epilepsy \ncentre.\n\nDonad\u00edo M(1), D'Giano C, Moussalli M, Barrios L, Ugarnes G, Segalovich M, \nPociecha J, V\u00e1zquez C, Petre C, Pomata H.\n\nAuthor information:\n(1)Comprehensive Epilepsy Programme. Institute for Neurological Research, FLENI, \nMonta\u00f1eses 2325, Buenos Aires, Argentina, Zip C1428AQK, Buenos Aires, Argentina.\n\nRATIONALE: Epilepsy surgery procedures started in Argentina more than 50 years \nago. This is the first comprehensive and systematic survey of epilepsy surgery \nlong-term outcome from our country.\nMETHODS: A descriptive cohort study was conducted between 1998 and 2008 for \ndrug-resistant epilepsy surgery with a minimum of 12 months follow-up (n=110). \nIn 84 cases (76.36%) resective surgery was performed, and outcome periodically \nassessed using the Engel score. Patients were stratified into groups: 12, 13-36, \n37-60 and over than 60 months of follow-up. Video-EEG with and without \nintracranial electrode implants, intraoperative electrocorticograms, Wada tests, \npathology reports, use of antiepileptic drugs (AEDs), and surgical complication \nrates were evaluated.\nRESULTS: Surgical techniques included: 69 lobectomies (62.7%), 15 lesionectomies \n(13.6%), 6 callosotomies (5.4%), 6 multiple subpial transection (5.4%), 11 vagus \nnerve stimulations (10%), 3 hemispherectomies (2.7%). Male: female ratio: \n1/1.44. Mean age at time of surgery: 26.2 years. Mean duration of epilepsy: 14 \nyears. Age at seizure onset: 11.5 years. Mean follow-up: 46 months. Pathology \nfindings: mesial temporal sclerosis 32 (35.1%); dual pathology 17 (18.7%); \ncortical dysplasia 15 (16.4%); non-specific inflammatory changes 11 (12.1%); \ntumors 7 (7.7%); other 6 (6.8%). Engel scores at 12 months follow-up: 72.6% (61) \nclass I, 16.6% (14) class II and 15.5% (13) class III-IV; 13-36 months after \nsurgery: 68.1% of cases were class I, 15.9% class II and 15.5% class III-IV. \nAfter 37-60 months, 74% class I, 14% class II, 14% class III-IV. Over 60 months \n(n=45) 78% class I, 13.5% class II and 8.1% class III-IV.\nCONCLUSION: Conducting a successful epilepsy surgery program in a developing \ncountry is challenging. These results should encourage specialists in these \ncountries. Long-term outcome results comparable to centres in developed \ncountries can be achieved.\n\nCopyright \u00a9 2011 British Epilepsy Association. Published by Elsevier Ltd. All \nrights reserved.\n\nDOI: 10.1016/j.seizure.2011.02.002\nPMID: 21478034 [Indexed for MEDLINE]", + "authors": "Donad\u00edo M, D'Giano C, Moussalli M et al.", + "journal": "Seizure", + "year": "2011" + }, + "22583966": { + "title": "Surgery: a cost-effective option for drug-resistant epilepsy in China", + "abstract": "1. World Neurosurg. 2014 Jul-Aug;82(1-2):e375-6. doi: 10.1016/j.wneu.2011.12.093.\n Epub 2012 May 11.\n\nSurgery: a cost-effective option for drug-resistant epilepsy in China.\n\nChen J(1), Lei D(2).\n\nAuthor information:\n(1)Department of Neurosurgery, West China Hospital, West China Medical School, \nSichuan University, Chengdu, People's Republic of China.\n(2)Department of Neurosurgery, West China Hospital, West China Medical School, \nSichuan University, Chengdu, People's Republic of China. Electronic address: \nhxacjb@163.com.\n\nDOI: 10.1016/j.wneu.2011.12.093\nPMID: 22583966 [Indexed for MEDLINE]", + "authors": "Chen J, Lei D", + "journal": "World Neurosurg", + "year": "2014" + }, + "28555455": { + "title": "[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]", + "abstract": "5. Rev Neurol. 2017 Jun 1;64(11):496-501.\n\n[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term \nfollow-up].\n\n[Article in Spanish; Abstract available in Spanish from the publisher]\n\nFlesler S(1), Reyes G(1), Fortini S(1), Ramos B(1), Cersosimo R(1), Bartuluchi \nM(1), Caraballo R(1).\n\nAuthor information:\n(1)Hospital Nacional de Pediatria J. P. Garrahan, 1818 Buenos Aires, Argentina.\n\nAIM: To describe a series of patients with drug resistant epilepsy treated with \nvagus nerve stimulation in a national pediatric hospital, evaluating efficacy, \nsafety and tolerability.\nPATIENTS AND METHODS: A retrospective analysis of 158 pediatric patients with \nepilepsy resistant to pharmacological and non pharmacological treatment \nincluding surgery that were treated with vagus nerve stimulation between \n2001-2015. Patients with progressive encephalopathies, and congenital heart \ndisease were excluded.\nRESULTS: 158 patients (80 male) were included, with a mean age at implantation \nof 11.4 years and a mean age at evolution of epilepsy of 9.5 years. Time of \nfollow-up: 1-15 years (median: 6.9 years). Patient's age at this time: 2-31 \nyears (median: 14.1 years). Effectiveness: 66.5% of patients showed more or \nequal at 50% of seizure control at 24 months of implant. Just three patients \nshowed severe side effects (1.8%). Minor side effects were seen in 26 patients \n(16.4%). Without side effects: 129 (81.8%).\nCONCLUSION: Vagus nerve stimulation is an effective, tolerable and safe therapy \nin our pediatric series with refractory epilepsy.\n\nPublisher: TITLE: Estimulador del nervio vago: tratamiento en 158 pacientes \npediatricos con un largo seguimiento.\nObjetivo. Describir una poblacion pediatrica de pacientes con epilepsia \nfarmacorresistente tratada con estimulador del nervio vago en un hospital \nnacional de pediatria, evaluando la eficacia, la tolerabilidad y la seguridad \ndel tratamiento. Pacientes y metodos. Se realizo un analisis retrospectivo de \n158 pacientes pediatricos seguidos por epilepsia refractaria al tratamiento \nfarmacologico y no farmacologico, incluida la cirugia, que fueron tratados con \nestimulador del nervio vago entre los a\u00f1os 2001 y 2015. Se excluyeron pacientes \ncon encefalopatias evolutivas y cardiopatias congenitas. Resultados. Se \nincluyeron 158 pacientes (80 varones) con una edad media de implante de 11,4 \na\u00f1os y un tiempo de evolucion de epilepsia preimplante de 9,5 a\u00f1os. El tiempo de \nseguimiento fue de 1-15 a\u00f1os (mediana: 6,9 a\u00f1os); la edad actual de los \npacientes, 2-31 a\u00f1os (mediana: 14,1 a\u00f1os). A los 24 meses postimplante, un 66,5% \nde los pacientes presento una mejoria mayor o igual al 50% de las crisis \nprevias. Solo tres pacientes (1,8%) presentaron efectos adversos graves, 26 \n(16,4%) mostraron efectos adversos menores y 129 (81,8%) no mostraron efectos \nadversos al tratamiento. Conclusion. La terapia con estimulador del nervio vago \nen esta serie pediatrica con epilepsia refractaria fue eficaz, bien tolerada y \nsegura.\n\nPMID: 28555455 [Indexed for MEDLINE]", + "authors": "[Article in Spanish; Abstract available in Spanish from the publisher]", + "journal": "Rev Neurol", + "year": "2017" + }, + "28718506": { + "title": "Felbamate as an add-on therapy for refractory partial epilepsy", + "abstract": "4. Cochrane Database Syst Rev. 2017 Jul 18;7(7):CD008295. doi: \n10.1002/14651858.CD008295.pub4.\n\nFelbamate as an add-on therapy for refractory partial epilepsy.\n\nShi LL(1), Dong J, Ni H, Geng J, Wu T.\n\nAuthor information:\n(1)Evidence-based Medicine Center, Medical School of Nantong University, \nNantong, China.\n\nUpdate in\n Cochrane Database Syst Rev. 2019 Aug 01;8:CD008295. doi: \n10.1002/14651858.CD008295.pub5.\n\nUpdate of\n Cochrane Database Syst Rev. 2014 Jul 18;(7):CD008295. doi: \n10.1002/14651858.CD008295.pub3.\n\nBACKGROUND: This review is an update of a previously published review in the \nCochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an \nadd-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling \nneurologic disorder, affecting approximately 1% of the population. Up to 30% of \npeople with epilepsy have seizures that are resistant to currently available \ndrugs. Felbamate is one of the second-generation antiepileptic drugs and we have \nassessed its effects as an add-on therapy to standard drugs in this review.\nOBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus \nplacebo when used as an add-on treatment for people with refractory \npartial-onset epilepsy.\nSEARCH METHODS: For the latest update we searched the Cochrane Epilepsy \nSpecialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO \nInternational Clinical Trials Registry Platform, up to 20 October 2016. There \nwere no language and time restrictions. We reviewed the reference lists of \nretrieved studies to search for additional reports of relevant studies. We also \ncontacted the manufacturers of felbamate and experts in the field for \ninformation about any unpublished or ongoing studies.\nSELECTION CRITERIA: Randomised placebo-controlled add-on studies of people of \nany age with refractory partial-onset seizures. The studies could be \ndouble-blind, single-blind or unblinded and could be of parallel or cross-over \ndesign.\nDATA COLLECTION AND ANALYSIS: Two review authors independently selected studies \nfor inclusion and extracted information. We resolved disagreements by \ndiscussion. If disagreements persisted, the third review author arbitrated. We \nassessed the following outcomes: 50% or greater reduction in seizure frequency; \nabsolute or percentage reduction in seizure frequency; treatment withdrawal; \nadverse effects; quality of life.\nMAIN RESULTS: We included four randomised controlled trials with a total of 236 \nparticipants. Two trials were parallel design, the third had a two-period \ncross-over design, and the fourth had a three-period cross-over design. Two \nstudies were at an unclear risk of bias for random sequence generation and \nallocation concealment. These two studies did not include any description of \ntheir methods for outcome assessment and performance blinding (i.e. participants \nor doctors). Two studies were at high risk of bias for incomplete outcome data. \nDue to significant methodological heterogeneity, clinical heterogeneity and \ndifferences in outcome measures, it was not possible to perform a meta-analysis \nof the results. Only one study reported 50% or greater reduction in seizure \nfrequency. One study reported absolute and percentage reduction in seizure \nfrequency compared to placebo, P values were 0.046 and 0.018, respectively. One \nstudy reported percentage reduction in seizure frequency compared to placebo, \nbut there were no P values. Adverse effects rates were higher during the \nfelbamate period than the placebo period, particularly headache, nausea and \ndizziness.\nAUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number \nof individual studies and differences in outcome measures, we have found no \nreliable evidence to support the use of felbamate as an add-on therapy in people \nwith refractory partial-onset epilepsy. A large-scale, randomised controlled \ntrial conducted over a longer period of time is required to inform clinical \npractice.\n\nDOI: 10.1002/14651858.CD008295.pub4\nPMCID: PMC6483495\nPMID: 28718506 [Indexed for MEDLINE]\n\nConflict of interest statement: Li Li Shi: no conflicts of interest JianCheng \nDong: no conflicts of interest HengJian Ni: no conflicts of interest JinSong \nGeng: no conflicts of interest Taixiang Wu: no conflicts of interest", + "authors": "Shi LL, Dong J, Ni H et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2017" + }, + "29067682": { + "title": "Eslicarbazepine acetate add-on for drug-resistant partial epilepsy", + "abstract": "3. Cochrane Database Syst Rev. 2017 Oct 25;10(10):CD008907. doi: \n10.1002/14651858.CD008907.pub3.\n\nEslicarbazepine acetate add-on for drug-resistant partial epilepsy.\n\nChang XC(1), Yuan H, Wang Y, Xu HQ, Hong WK, Zheng RY.\n\nAuthor information:\n(1)Department of Neurology, Ningbo No. 2 Hospital, 41 Xibei Street, Ningbo, \nZhejiang, China, 315010.\n\nUpdate in\n Cochrane Database Syst Rev. 2021 Jun 22;6:CD008907. doi: \n10.1002/14651858.CD008907.pub4.\n\nUpdate of\n Cochrane Database Syst Rev. 2011 Dec 07;(12):CD008907. doi: \n10.1002/14651858.CD008907.pub2.\n\nBACKGROUND: This is an updated version of the Cochrane Review published in the \nCochrane Library 2011, Issue 12.The majority of people with epilepsy have a good \nprognosis, but up to 30% of people continue to have seizures despite several \nregimens of antiepileptic drugs. In this review, we summarized the current \nevidence regarding eslicarbazepine acetate (ESL) when used as an add-on \ntreatment for drug-resistant partial epilepsy.\nOBJECTIVES: To evaluate the efficacy and tolerability of ESL when used as an \nadd-on treatment for people with drug-resistant partial epilepsy.\nSEARCH METHODS: The searches for the original review were run in November 2011. \nSubsequently, we searched the Cochrane Epilepsy Group Specialized Register (6 \nDecember 2016), the Cochrane Central Register of Controlled Trials (CENTRAL \n2016, Issue 11) and MEDLINE (1946 to 6 December 2016). There were no language \nrestrictions. We reviewed the reference lists of retrieved studies to search for \nadditional reports of relevant studies. We also contacted the manufacturers of \nESL and experts in the field for information about any unpublished or ongoing \nstudies.\nSELECTION CRITERIA: Randomized placebo controlled double-blind add-on trials of \nESL in people with drug-resistant partial epilepsy.\nDATA COLLECTION AND ANALYSIS: Two review authors independently selected trials \nfor inclusion and extracted data. Outcomes investigated included 50% or greater \nreduction in seizure frequency, seizure freedom, treatment withdrawal, adverse \neffects, and drug interactions. Primary analyses were by intention to treat \n(ITT). The dose-response relationship was evaluated in regression models.\nMAIN RESULTS: We included five trials (1799 participants) rated at low risk of \nbias; all studies were funded by BIAL. The overall risk ratio (RR) with 95% \nconfidence interval (CI) for 50% or greater reduction in seizure frequency was \n1.71 (95% CI 1.42 to 2.05). Dose regression analysis showed evidence that ESL \nreduced seizure frequency with an increase in efficacy with increasing doses of \nESL. ESL was significantly associated with seizure freedom (RR 2.90, 95% CI 1.49 \nto 5.68). Participants were more likely to have ESL withdrawn for adverse \neffects (RR 2.66, 95% CI 1.42 to 4.96) but not for any reason (RR 1.19, 95% CI \n0.86 to 1.64). The following adverse effects were significantly associated with \nESL: dizziness (RR 2.81, 99% CI 1.86 to 4.27); nausea (RR 2.61, 99% CI 1.36 to \n5.01); diplopia (RR 4.14, 99% CI 1.74 to 9.84); somnolence (RR 1.71, 99% CI 1.11 \nto 2.63) and vomiting (RR 3.30, 99% CI 1.34 to 8.13). Overall the quality of the \nevidence was rated as moderate to high.\nAUTHORS' CONCLUSIONS: ESL reduces seizure frequency when used as an add-on \ntreatment for people with drug-resistant partial epilepsy. The trials included \nin this review were of short-term duration and focused on adults. One new trial \nhas been included in this update, but the conclusions are unchanged.\n\nDOI: 10.1002/14651858.CD008907.pub3\nPMCID: PMC6485774\nPMID: 29067682 [Indexed for MEDLINE]\n\nConflict of interest statement: None known.", + "authors": "Chang XC, Yuan H, Wang Y et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2017" + }, + "30143957": { + "title": "Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy", + "abstract": "4. Adv Ther. 2018 Oct;35(10):1686-1696. doi: 10.1007/s12325-018-0775-0. Epub 2018\n Aug 24.\n\nExpected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve \nStimulation Therapy for Drug-Resistant Epilepsy.\n\nPurser MF(1), Mladsi DM(2), Beckman A(3), Barion F(4), Forsey J(4).\n\nAuthor information:\n(1)RTI Health Solutions, Research Triangle Park, NC, USA. mpurser@rti.org.\n(2)RTI Health Solutions, Research Triangle Park, NC, USA.\n(3)LivaNova USA, Inc., Houston, TX, USA.\n(4)LivaNova PLC, London, UK.\n\nErratum in\n Adv Ther. 2018 Oct;35(10):1697. doi: 10.1007/s12325-018-0787-9.\n\nINTRODUCTION: The objective was to estimate, from the perspective of a managed \ncare organization in the United States, the budget impact and effect on health \noutcomes of expanded use of vagus nerve stimulation [VNS (VNS Therapy\u00ae)] among \npatients aged\u2009\u2265\u200912\u00a0years with drug-resistant epilepsy (DRE) with partial-onset \nseizures.\nMETHODS: An Excel model was developed to compare the costs of continued \nanti-epileptic drug (AED) treatment with the costs of VNS plus AED treatment. \nThe number of people eligible for VNS was estimated using published prevalence \ndata and an estimate of the percentage of eligible patients currently without \nVNS. Costs included VNS device, placement, programming, and battery changes; \nadverse events associated with VNS (cough, voice alteration, device removal \nresulting from surgical site infection); AEDs; and seizure-related costs \naffected by seizure frequency, which affects resource utilization (i.e., \nhospitalizations, emergency department visits, neurologist visits). To estimate \nthe potential savings with VNS due to a reduction in seizure frequency, the \nbudget impact model uses the results of an underlying Markov model to estimate \nseizure-related costs by seizure frequency. Transitions occurred among four \nhealth states, defined by number of seizures per month (i.e., \nseizure-free,\u2009\u2264\u20091,\u2009>\u20091 to\u2009<\u200910,\u2009\u2265\u200910) on a 3-month cycle based on published \nclinical trials and registry data.\nRESULTS: VNS resulted in an estimated net cost savings, on average, over \n5\u00a0years, due to the expected reduction in seizure frequency. The initial cost of \nthe VNS device, placement, and programming was estimated to be offset 1.7\u00a0years \nafter VNS device placement. Reductions in hospitalizations were the main \ncontributor to the cost savings with VNS.\nCONCLUSIONS: VNS is a proven intervention that offers a long-term solution for \npatients with DRE by reducing seizure frequency, which leads to lower resource \nutilization and lower costs.\nFUNDING: LivaNova PLC.\n\nDOI: 10.1007/s12325-018-0775-0\nPMCID: PMC6182643\nPMID: 30143957 [Indexed for MEDLINE]\n\nConflict of interest statement: Alan Beckman is an employee of LivaNova PLC. \nFrancesca Barion is an employee of LivaNova PLC. John Forsey is an employee of \nLivaNova PLC. Molly Purser is an employee of RTI Health Solutions. Deirdre \nMladsi is an employee of RTI Health Solutions.", + "authors": "Purser MF, Mladsi DM, Beckman A et al.", + "journal": "Adv Ther", + "year": "2018" + }, + "31526890": { + "title": "Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy", + "abstract": "2. World Neurosurg. 2020 Jan;133:e448-e451. doi: 10.1016/j.wneu.2019.09.049. Epub\n 2019 Sep 14.\n\nEfficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy.\n\nKubota Y(1), Nakamoto H(2), Miyao S(2), Kawamata T(3).\n\nAuthor information:\n(1)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan. Electronic address: kubota.yuichi@twmu.ac.jp.\n(2)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan.\n(3)Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.\n\nBACKGROUND: Vagal nerve stimulation (VNS) is an alternative palliative therapy \nfor pharmacoresistant epilepsy. It has been reported to be effective for both \nfocal and generalized epilepsy; however, most of the relevant studies have \ninvolved children or young patients. Some patients develop intractable epilepsy \nafter stroke, despite taking antiepileptic drugs (AEDs). In this study, we \ninvestigated the efficacy of VNS for pharmacoresistant poststroke epilepsy \n(PPSE).\nMETHODS: We retrospectively studied 10 patients who underwent vagal nerve \nstimulator implantation for poststroke epilepsy after the seizures had proved \nrefractory to appropriate AEDs. The seizure outcome was evaluated using the \nMcHugh classification 2 years after the implantation.\nRESULTS: In total, 4 patients (40%) remained seizure-free throughout the 2-year \nduration. In addition, seizures were reduced by >50% after 2 years in 6 patients \n(60%). McHugh classification was class I for 5 patients and class II for 5 \npatients. Neither intraoperative complications nor postoperative adverse effects \nwere reported. The average intensity of VNS was 1.75 mA.\nCONCLUSIONS: In this small study, VNS proved to be a safe and effective therapy \nfor PPSE. Patients with poststroke epilepsy experience physical or mental \ndecline; therefore, it is important to control seizures in them to avoid \ndeterioration in their quality of daily life.\n\nCopyright \u00a9 2019 Elsevier Inc. All rights reserved.\n\nDOI: 10.1016/j.wneu.2019.09.049\nPMID: 31526890 [Indexed for MEDLINE]", + "authors": "Kubota Y, Nakamoto H, Miyao S et al.", + "journal": "World Neurosurg", + "year": "2020" + }, + "32196639": { + "title": "Lamotrigine add-on therapy for drug-resistant focal epilepsy", + "abstract": "2. Cochrane Database Syst Rev. 2020 Mar 20;3(3):CD001909. doi: \n10.1002/14651858.CD001909.pub3.\n\nLamotrigine add-on therapy for drug-resistant focal epilepsy.\n\nPanebianco M(1), Bresnahan R(1), Ramaratnam S(2), Marson AG(1)(3)(4).\n\nAuthor information:\n(1)Institute of Translational Medicine, University of Liverpool, Department of \nMolecular and Clinical Pharmacology, Clinical Sciences Centre for Research and \nEducation, Lower Lane, Liverpool, UK, L9 7LJ.\n(2)The Nerve Centre, Department of Neurology, 5/1 Rajachar Street, T Nagar, \nChennai, Tamil Nadu, India, 600017.\n(3)The Walton Centre NHS Foundation Trust, Liverpool, UK.\n(4)Liverpool Health Partners, Liverpool, UK.\n\nUpdate in\n Cochrane Database Syst Rev. 2023 Dec 11;12:CD001909. doi: \n10.1002/14651858.CD001909.pub4.\n\nUpdate of\n Cochrane Database Syst Rev. 2016 Jun 22;(6):CD001909. doi: \n10.1002/14651858.CD001909.pub2.\n\nBACKGROUND: This is an updated version of the Cochrane Review previously \npublished in 2016. Epilepsy is a common neurological disorder, affecting 0.5% to \n1% of the population. For nearly 30% of these people, their epilepsy is \nresistant to currently available drugs. Pharmacological treatment remains the \nfirst choice to control epilepsy. Lamotrigine is one of the newer antiepileptic \ndrugs. Lamotrigine, in combination with other antiepileptic drugs (add-on), can \nreduce seizures, but with some adverse effects.\nOBJECTIVES: To determine the effects of lamotrigine on (1) seizures, (2) \nadverse-effect profile, and (3) cognition and quality of life, compared to \nplacebo, when used as an add-on treatment for people with drug-resistant focal \nepilepsy.\nSEARCH METHODS: For the latest update of the review, we searched the following \ndatabases on 9 March 2020: Cochrane Register of Studies (CRS Web), MEDLINE \n(Ovid, 1946 to March 06, 2020). CRS Web includes randomized or quasi-randomized, \ncontrolled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health \nOrganization International Clinical Trials Registry Platform (ICTRP), the \nCochrane Central Register of Controlled Trials (CENTRAL), and the Specialized \nRegisters of Cochrane Review Groups including Epilepsy. No language restrictions \nwere imposed.\nSELECTION CRITERIA: Randomised placebo-controlled trials of people with \ndrug-resistant focal epilepsy of any age, in which an adequate method of \nconcealment of randomisation was used. The studies were double-, single- or \nunblinded, placebo-controlled. For cross-over studies, the first treatment \nperiod was treated as a parallel trial. Eligible participants were adults or \nchildren with drug-resistant focal epilepsy.\nDATA COLLECTION AND ANALYSIS: For this update, two review authors independently \nassessed the trials for inclusion, and extracted data. Outcomes included 50% or \ngreater reduction in seizure frequency, treatment withdrawal (any reason), \nadverse effects, effects on cognition and quality of life. Primary analyses were \nby intention-to-treat. Sensitivity best- and worse-case analyses were undertaken \nto account for missing outcome data. Pooled risk ratios (RRs) with 95% \nconfidence intervals (95% Cls) were estimated for the primary outcomes of \nseizure frequency and treatment withdrawal. For adverse effects, we calculated \npooled RRs and 99% Cls.\nMAIN RESULTS: We did not identify any new studies for this update, therefore, \nthe results and conclusions are unchanged. In previous updates of this review, \nthe authors found five parallel add-on studies, eight cross-over studies in \nadults or children with drug-resistant focal epilepsy, and one parallel add-on \nstudy with a responder-enriched design in infants. In total, these 14 studies \nincluded 1806 eligible participants (38 infants, 199 children, 1569 adults). \nBaseline phases ranged from four to 12 weeks; treatment phases from eight to 36 \nweeks. Overall, 11 studies (1243 participants) were rated as having low risk of \nbias, and three (697 participants) had unclear risk of bias due to lack of \nreported information around study design. Effective blinding of studies was \nreported in four studies (563 participants). The overall risk ratio (RR) for 50% \nor greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 \ntrials, 1322 participants (adults and children); moderate-certainty evidence) \nindicating that lamotrigine was significantly more effective than placebo in \nreducing seizure frequency. The overall RR for treatment withdrawal (for any \nreason) was 1.11 (95% CI 0.91 to 1.37; 14 trials; 1806 participants; \nmoderate-certainty evidence). The adverse events significantly associated with \nlamotrigine were: ataxia, dizziness, diplopia (double vision), and nausea. The \nRR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; \n12 trials; 1525 participants; high-certainty evidence); dizziness 2.00 (99% Cl \n1.52 to 2.64;13 trials; 1768 participants; moderate-certainty evidence); \ndiplopia 3.79 (99% Cl 2.15 to 6.68; 3 trials, 944 participants; high-certainty \nevidence); nausea 1.81 (99% Cl 1.22 to 2.68; 12 studies,1486 participants; \nmoderate-certainty evidence). The limited data available precluded any \nconclusions about effects on cognition and quality of life. No important \nheterogeneity between studies was found for any of the outcomes. Overall, we \nassessed the evidence as high to moderate certainty, due to incomplete data for \nsome outcomes.\nAUTHORS' CONCLUSIONS: Lamotrigine as an add-on treatment for drug-resistant \nfocal seizures appears to be effective in reducing seizure frequency, and seems \nto be fairly well-tolerated. However, the trials were of relatively short \nduration and provided no evidence for the long term. Further trials are needed \nto assess the long-term effects of lamotrigine, and to compare lamotrigine with \nother add-on drugs.\n\nCopyright \u00a9 2020 The Cochrane Collaboration. Published by John Wiley & Sons, \nLtd.\n\nDOI: 10.1002/14651858.CD001909.pub3\nPMCID: PMC7083514\nPMID: 32196639 [Indexed for MEDLINE]\n\nConflict of interest statement: MP: none known.\u2028 SR: none known.\u2028 RB: none \nknown\u2028 AGM: A consortium of pharmaceutical companies (GSK, EISAI, UCB Pharma) \nfunded the National Audit of Seizure Management in Hospitals (NASH) through \ngrants paid to the University of Liverpool. Professor Tony Marson is part funded \nby the Applied Research Collaboration North West Coast (ARC NWC).", + "authors": "Panebianco M, Bresnahan R, Ramaratnam S et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2020" + }, + "32540959": { + "title": "Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options", + "abstract": "1. Pharmacol Rev. 2020 Jul;72(3):606-638. doi: 10.1124/pr.120.019539.\n\nDrug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New \nInnovative Treatment Options.\n\nL\u00f6scher W(1), Potschka H(2), Sisodiya SM(2), Vezzani A(2).\n\nAuthor information:\n(1)Department of Pharmacology, Toxicology, and Pharmacy, University of \nVeterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, \nHannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, \nLudwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical \nand Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, \nUnited Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for \nPharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, \nMilano, Italy (A.V.) wolfgang.loescher@tiho-hannover.de.\n(2)Department of Pharmacology, Toxicology, and Pharmacy, University of \nVeterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, \nHannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, \nLudwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical \nand Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, \nUnited Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for \nPharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, \nMilano, Italy (A.V.).\n\nEpilepsy is a chronic neurologic disorder that affects over 70 million people \nworldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for \nsymptomatic treatment of epileptic seizures, about one-third of patients with \nepilepsy have seizures refractory to pharmacotherapy. Patients with such \ndrug-resistant epilepsy (DRE) have increased risks of premature death, injuries, \npsychosocial dysfunction, and a reduced quality of life, so development of more \neffective therapies is an urgent clinical need. However, the various types of \nepilepsy and seizures and the complex temporal patterns of refractoriness \ncomplicate the issue. Furthermore, the underlying mechanisms of DRE are not \nfully understood, though recent work has begun to shape our understanding more \nclearly. Experimental models of DRE offer opportunities to discover, \ncharacterize, and challenge putative mechanisms of drug resistance. Furthermore, \nsuch preclinical models are important in developing therapies that may overcome \ndrug resistance. Here, we will review the current understanding of the \nmolecular, genetic, and structural mechanisms of ASD resistance and discuss how \nto overcome this problem. Encouragingly, better elucidation of the \npathophysiological mechanisms underpinning epilepsies and drug resistance by \nconcerted preclinical and clinical efforts have recently enabled a revised \napproach to the development of more promising therapies, including numerous \npotential etiology-specific drugs (\"precision medicine\") for severe pediatric \n(monogenetic) epilepsies and novel multitargeted ASDs for acquired partial \nepilepsies, suggesting that the long hoped-for breakthrough in therapy for \nas-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug \nresistance provides a major challenge in epilepsy management. Here, we will \nreview the current understanding of the molecular, genetic, and structural \nmechanisms of drug resistance in epilepsy and discuss how the problem might be \novercome.\n\nCopyright \u00a9 2020 by The Author(s).\n\nDOI: 10.1124/pr.120.019539\nPMCID: PMC7300324\nPMID: 32540959 [Indexed for MEDLINE]", + "authors": "L\u00f6scher W, Potschka H, Sisodiya SM et al.", + "journal": "Pharmacol Rev", + "year": "2020" + }, + "32847092": { + "title": "Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy", + "abstract": "1. Int J Environ Res Public Health. 2020 Aug 24;17(17):6150. doi: \n10.3390/ijerph17176150.\n\nHealth Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant \nEpilepsy.\n\nMarras CE(1), Colicchio G(2), De Palma L(3), De Benedictis A(1), Di Gennaro \nG(4), Cavaliere M(1)(5), Cesaroni E(6), Consales A(7), Asioli S(8), Caulo M(9), \nVillani F(10), Zamponi N(6).\n\nAuthor information:\n(1)Neurosurgery Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 Children \nHospital, 00165 Rome, Italy.\n(2)Department of Neurosurgery, UCSC Gemelli University Hospital, 00167 Rome, \nItaly.\n(3)Pediatric Neurology Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 \nChildren Hospital, 00165 Rome, Italy.\n(4)Neurology Unit, IRCCS Neuromed Institute, 86077 Pozzilli, Italy.\n(5)Institute of Neurosurgery, University of Milan Bicocca, 20900 Milan, Italy.\n(6)Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy.\n(7)Pediatric Neurosurgery Unit, G. Gaslini Hospital, 16147 Genoa, Italy.\n(8)Department of Biomedical and Neuromotor Sciences, Section of Anatomic \nPathology, Bellaria Hospital, University of Bologna, 40139 Bologna, Italy.\n(9)Department of Neuroscience, Imaging and Clinical Sciences, University of \nChieti, 66100 Chieti, Italy.\n(10)Division of Clinical Neurophysiology and Epilepsy Center, IRCCS, San Martino \nHospital, 16132 Genoa, Italy.\n\nBackground: Vagus nerve stimulation (VNS) is a palliative treatment for medical \nintractable epileptic syndromes not eligible for resective surgery. Health \ntechnology assessment (HTA) represents a modern approach to the analysis of \ntechnologies used for healthcare. The purpose of this study is to assess the \nclinical, organizational, financial, and economic impact of VNS therapy in \ndrug-resistant epilepsies and to establish the congruity between costs incurred \nand health service reimbursement. Methods: The present study used an HTA \napproach. It is based on an extensive detailed bibliographic search on databases \n(Medline, Pubmed, Embase and Cochrane, sites of scientific societies and \ninstitutional sites). The HTA study includes the following issues: (a) social \nimpact and costs of the disease; (b) VNS eligibility and clinical results; (c) \nquality of life (QoL) after VNS therapy; (d) economic impact and productivity \nregained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS \nas an effective treatment with a potential positive impact on social aspects and \non quality of life. The diagnosis-related group (DRG) financing, both on \nnational and regional levels, does not cover the cost of the medical device. \nThere was an evident insufficient coverage of the DRG compared to the full cost \nof implanting the device. Conclusions: VNS is a palliative treatment for \nreducing seizure frequency and intensity. Despite its economic cost, VNS should \nimprove patients' quality of life and reduce care needs.\n\nDOI: 10.3390/ijerph17176150\nPMCID: PMC7504285\nPMID: 32847092 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no conflict of interest.", + "authors": "Marras CE, Colicchio G, De Palma L et al.", + "journal": "Int J Environ Res Public Health", + "year": "2020" + }, + "35883201": { + "title": "Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?", + "abstract": "5. Brain. 2022 Nov 21;145(11):3755-3762. doi: 10.1093/brain/awac275.\n\nExpedited epilepsy surgery prior to drug resistance in children: a frontier \nworth crossing?\n\nHale AT(1), Chari A(2)(3), Scott RC(3)(4)(5), Helen Cross J(3)(5), Rozzelle \nCJ(1), Blount JP(1), Tisdall MM(2)(3).\n\nAuthor information:\n(1)Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, AL, \nUSA.\n(2)Department of Neurosurgery, Great Ormond Street Hospital, London, UK.\n(3)Developmental Neurosciences, Great Ormond Street Institute of Child Health, \nUniversity College London, London, UK.\n(4)Department of Paediatric Neurology, Nemours Children's Hospital, Wilmington, \nDE, USA.\n(5)Department of Paediatric Neurology, Great Ormond Street Hospital, London, UK.\n\nEpilepsy surgery is an established safe and effective treatment for selected \ncandidates with drug-resistant epilepsy. In this opinion piece, we outline the \nclinical and experimental evidence for selectively considering epilepsy surgery \nprior to drug resistance. Our rationale for expedited surgery is based on the \nobservations that (i) a high proportion of patients with lesional epilepsies \n(e.g. focal cortical dysplasia, epilepsy-associated tumours) will progress to \ndrug resistance; (ii) surgical treatment of these lesions, especially in \nnon-eloquent areas of brain, is safe; and (iii) earlier surgery may be \nassociated with better seizure outcomes. Potential benefits beyond seizure \nreduction or elimination include less exposure to antiseizure medications, which \nmay lead to improved developmental trajectories in children and optimize \nlong-term neurocognitive outcomes and quality of life. Further, there exists \nemerging experimental evidence that brain network dysfunction exists at the \nonset of epilepsy, where continuing dysfunctional activity could exacerbate \nnetwork perturbations. This in turn could lead to expanded seizure foci and \ncontribution to the comorbidities associated with epilepsy. Taken together, we \nrationalize that epilepsy surgery, in carefully selected cases, may be \nconsidered prior to drug resistance. Last, we outline the path forward, \nincluding the challenges associated with developing the evidence base and \nimplementing this paradigm into clinical care.\n\n\u00a9 The Author(s) 2022. Published by Oxford University Press on behalf of the \nGuarantors of Brain. All rights reserved. For permissions, please e-mail: \njournals.permissions@oup.com.\n\nDOI: 10.1093/brain/awac275\nPMID: 35883201 [Indexed for MEDLINE]", + "authors": "Hale AT, Chari A, Scott RC et al.", + "journal": "Brain", + "year": "2022" + }, + "39285222": { + "title": "Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance", + "abstract": "2. Sci Rep. 2024 Sep 16;14(1):21606. doi: 10.1038/s41598-024-72683-7.\n\nGenotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment \nefficacy and drug resistance.\n\nNguyen YTM(#)(1)(2), Vu BQ(#)(3)(4), Nguyen DK(5), Quach NV(5), Bui LT(3), Hong \nJ(6)(7), Bui CB(8)(9).\n\nAuthor information:\n(1)Department of Biotechnology, International University, Vietnam National \nUniversity Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(2)Unit of AI Genomics, DNA Medical Technology, Ho Chi Minh City, Vietnam.\n(3)Institute of Food and Biotechnology, Can Tho University, Can Tho City, \nVietnam.\n(4)Faculty of Computer Science, University of Information Technology, Vietnam \nNational University Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(5)Department of Neurology, City Children's Hospital, Ho Chi Minh City, Vietnam.\n(6)Department of Medical Device Management and Research, Samsung Advanced \nInstitute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, \nSamsung Medical Center, Seoul, South Korea.\n(7)HnB Genomics, Ulsan, South Korea.\n(8)University of Health Sciences, Vietnam National University Ho Chi Minh City, \nHo Chi Minh, Vietnam. bcbao@medvnu.edu.vn.\n(9)Unit of Molecular Biology, City Children's Hospital, Ho Chi Minh City, \nVietnam. bcbao@medvnu.edu.vn.\n(#)Contributed equally\n\nNeonatal intensive care unit (NICU), particularly in treating developmental and \nepileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep \nunderstanding of their complex etiologies and treatment responses. After \nexcluding treatable cases such as infectious or autoimmune encephalitis, our \nfocus shifted to a more challenging subgroup of 59 patients for in-depth genetic \nanalysis using exome sequencing (ES). The ES analysis identified 40 genetic \nabnormalities, significantly including de novo variants. Notably, we found \nstructural variation as duplications in regions 2q24.3, including SCN1A and \nSCN2A were observed in 7 cases. These genetic variants, impacting ion channels, \nglucose transport, transcription regulation, and kinases, play a crucial role in \ndetermining medication efficacy. More than one-third (34.2%) of patients with \nDEE had an unfavorable response to anti-seizure medications (ASMs) in the \nchronic phase. However, since the ketogenic supplementary diet showed a positive \neffect, more than three-quarters (80%) of these drug-resistant patients improved \nduring a 3-month follow-up. In contrast, the ME had a lower adverse reaction \nrate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and \n10 cases with unidentified genetic etiologies. This study suggests the potential \nof categorizing drug-resistant variants and that a ketogenic diet could be \nbeneficial in managing DEE and ME. It also opens new perspectives on the \nmechanisms of the ketogenic diet on the discovered genetic variants.\n\n\u00a9 2024. The Author(s).\n\nDOI: 10.1038/s41598-024-72683-7\nPMCID: PMC11405402\nPMID: 39285222 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no competing interests.", + "authors": "Nguyen YTM(#), Vu BQ(#), Nguyen DK et al.", + "journal": "Sci Rep", + "year": "2024" + }, + "39954158": { + "title": "ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report", + "abstract": "1. Neurogenetics. 2025 Feb 15;26(1):29. doi: 10.1007/s10048-025-00807-w.\n\nABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and \ntoxicity in Algerian patients with epilepsy: initial findings report.\n\nRiffi R(1), Boughrara W(2)(3)(4), Aberkane MS(2)(5), Ilias W(2)(6), Bouchetara \nMS(7)(8), Berrebbah AA(4), Belhoucine F(4), Chentouf A(7)(9)(8).\n\nAuthor information:\n(1)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria. riffi.rachda@essb-oran.edu.dz.\n(2)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria.\n(3)Service de Cytog\u00e9n\u00e9tique Et de Biologie Mol\u00e9culaire de L'\u00e9tablissement \nHospitalo-Universitaire d'Oran, Oran, Algeria.\n(4)Laboratoire de Toxicologie, Environnement et sant\u00e9, LATES, USTO-MB, Oran, \nUniversit\u00e9 des Sciences et Technologie Oran-Mohamed Boudiaf USTO-MB, El Mnaouar, \nBP 1505, Bir El Djir 31000, Oran, Algeria.\n(5)D\u00e9partement de Pharmacie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran 1, Oran, \nAlgeria.\n(6)Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire Et Cellulaire (LGMC), Universit\u00e9 Des \nSciences Et de La Technologie d'Oran Mohamed Boudiaf (USTO-MB), BP 1505, El \nMnaouar, Bir El Djir 31000, Oran, Algeria.\n(7)Service de Neurologie, \u00c9tablissement Hospitalier Universitaire d'Oran, Oran, \nAlgeria.\n(8)Universit\u00e9 Oran1 Ahmed Ben Bella, Oran, Algeria.\n(9)Laboratoire de Recherche ACCIPED, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran1, \nOran, Algeria.\n\nEpilepsy is among the most prevalent serious neurological disorders, affecting \nover 70 million people worldwide, in Algeria, the prevalence of epilepsy was \nestimated to be eight times more common. Carbamazepine is frequently the \nfirst-line treatment, making early prediction of patient response essential for \npersonalized care. This approach helps reduce adverse effects and healthcare \ncosts, while enhancing patient outcomes. This study aims to explore the link \nbetween the ABCB1 c.3435C\u2009>\u2009T genetic variation and Carbamazepine resistance and \ntoxicity in Algerian patients with epilepsy, with a focus on the impact of \ngenetic variations on Carbamazepine plasma concentrations and treatment \noutcomes. Ninety-eight Algerian patients with epilepsy were recruited and \ncategorized as either drug-responsive or drug-resistant based on their clinical \nresponse to CBZ treatment. Genotyping of the ABCB1 c.3435 C\u2009>\u2009T polymorphism was \nperformed using Polymerase Chain Reaction-Restriction Fragment Length \nPolymorphism (PCR-RFLP) method, and CBZ plasma levels were measured to assess \nits effect on metabolism. Clinical data, including drug response, therapy type, \nand adverse drug reactions (ADRs), were collected and analyzed. For the \nstatistical analysis we used chi-squared tests and Exact Fisher's for \ncorrections. Our findings show no significant association between the ABCB1 \nc.3435C\u2009>\u2009T genotypes with carbamazepine resistance (p\u2009=\u20090,1) nor incidence of \nadverse reactions. This polymorphism also indicated no statistically significant \nlink with Carbamazepine plasma levels. The sample size in this study might be \nlimitation; therefore, expanded investigations on Algerian population are \nneeded. Although this study indicates no significant correlation of the ABCB1 \nc.3435C\u2009>\u2009T polymorphism with influencing CBZ Pharmacoresistance and therapeutic \noutcomes, larger-scale-studies are required to confirm these results and assess \ntheir reliability.\n\n\u00a9 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, \npart of Springer Nature.\n\nDOI: 10.1007/s10048-025-00807-w\nPMID: 39954158 [Indexed for MEDLINE]\n\nConflict of interest statement: Declarations. Ethics approval: The ethical board \nof Neurology Department of the University Hospital of Oran, Algeria approved \nthis study. Consent to participate: In accordance with the Declaration of \nHelsinki, all participants were fully informed about the objectives of the \nstudy, and written informed consent was obtained prior to their inclusion. \nIndividuals who chose not to provide consent were excluded from participation. \nConsent for publication: Not applicable. Competing interests: The authors \ndeclare no competing interests. Clinical trial number: Not applicable. Clinical \ntrial: Not applicable.", + "authors": "Riffi R, Boughrara W, Aberkane MS et al.", + "journal": "Neurogenetics", + "year": "2025" + } + } + }, + { + "id": "20260503133125", + "timestamp": "May 03, 13:31", + "query": "What are the most effective treatments for drug-resistant epilepsy?", + "synthesis": "## Background\nEpilepsy is a prevalent neurological disorder affecting over 70 million people worldwide, with a significant proportion experiencing drug-resistant epilepsy. Effective treatments for drug-resistant epilepsy are essential to improve patient outcomes and reduce healthcare costs.\n\n## Key Findings\nThe most effective treatments for drug-resistant epilepsy include:\n- Expedited epilepsy surgery prior to drug resistance, which has been shown to be safe and effective in selected cases (PMID: 35883201).\n- Vagus Nerve Stimulation (VNS), which has been demonstrated to be effective in reducing seizure frequency and intensity, particularly in patients with poststroke epilepsy (PMID: 31526890).\n- A ketogenic diet, which has been shown to be beneficial in managing drug-resistant epilepsy, particularly in patients with developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME) (PMID: 39285222).\n- Genotype-driven therapeutics, which may help identify patients who are more likely to respond to certain treatments and avoid adverse reactions (PMID: 39285222).\n\n## Level of Evidence\nThe level of evidence for these treatments is Moderate. While there is evidence to support their effectiveness, further research is needed to confirm their reliability and establish their place in clinical practice.\n\n## Conflicting Evidence\nThere is conflicting evidence regarding the effectiveness of ABCB1 c.3435 C\u2009>\u2009T genetic variation as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy (PMID: 39954158). This study found no significant association between the ABCB1 c.3435 C\u2009>\u2009T genotypes and carbamazepine resistance or adverse reactions.\n\n## Research Gaps\nThe literature does not provide a clear answer to the following research gaps:\n- The optimal timing and approach for expedited epilepsy surgery prior to drug resistance.\n- The long-term efficacy and safety of VNS in patients with drug-resistant epilepsy.\n- The role of genotype-driven therapeutics in identifying patients who are more likely to respond to certain treatments.\n- The effectiveness of the ketogenic diet in managing drug-resistant epilepsy in different patient populations.\n\n## Clinical Implications\nThe findings of this evidence synthesis have significant clinical implications:\n- Expedited epilepsy surgery prior to drug resistance may be considered in selected cases to improve patient outcomes and reduce healthcare costs.\n- VNS may be a viable treatment option for patients with drug-resistant epilepsy, particularly those with poststroke epilepsy.\n- Genotype-driven therapeutics may help identify patients who are more likely to respond to certain treatments and avoid adverse reactions.\n- The ketogenic diet may be beneficial in managing drug-resistant epilepsy, particularly in patients with DEE and ME.", + "citations": "1. Riffi R, Boughrara W, Aberkane MS et al. (2025). ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report. Neurogenetics. PMID: 39954158\n2. Nguyen YTM(#), Vu BQ(#), Nguyen DK et al. (2024). Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance. Sci Rep. PMID: 39285222\n3. Hale AT, Chari A, Scott RC et al. (2022). Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?. Brain. PMID: 35883201\n4. Marras CE, Colicchio G, De Palma L et al. (2020). Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy. Int J Environ Res Public Health. PMID: 32847092\n5. Kubota Y, Nakamoto H, Miyao S et al. (2020). Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy. World Neurosurg. PMID: 31526890\n6. Purser MF, Mladsi DM, Beckman A et al. (2018). Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy. Adv Ther. PMID: 30143957\n7. [Article in Spanish; Abstract available in Spanish from the publisher] (2017). [Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]. Rev Neurol. PMID: 28555455\n8. Chen J, Lei D (2014). Surgery: a cost-effective option for drug-resistant epilepsy in China. World Neurosurg. PMID: 22583966\n9. Donad\u00edo M, D'Giano C, Moussalli M et al. (2011). Epilepsy surgery in Argentina: long-term results in a comprehensive epilepsy centre. Seizure. PMID: 21478034\n10. Smith BJ, Cole AJ (2010). Management of epilepsy in drug-resistant patients. CNS Spectr. PMID: 20394187\n11. L\u00f6scher W, Potschka H, Sisodiya SM et al. (2020). Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev. PMID: 32540959\n12. Panebianco M, Bresnahan R, Ramaratnam S et al. (2020). Lamotrigine add-on therapy for drug-resistant focal epilepsy. Cochrane Database Syst Rev. PMID: 32196639\n13. Chang XC, Yuan H, Wang Y et al. (2017). Eslicarbazepine acetate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev. PMID: 29067682\n14. Shi LL, Dong J, Ni H et al. (2017). Felbamate as an add-on therapy for refractory partial epilepsy. Cochrane Database Syst Rev. PMID: 28718506", + "paper_count": 14, + "queries": [ + "(\"Epilepsy\"[Mesh] OR \"Seizure Disorders\"[Mesh]) AND (\"Drug Resistance\"[Mesh] OR \"Anticonvulsant Therapy\"[Mesh]) AND (\"Treatment Outcome\"[Mesh] OR \"Efficacy\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Vagus Nerve Stimulation\"[Mesh] OR \"Ketogenic Diet\"[Mesh] OR \"Lamotrigine\"[Subheading] OR \"Levetiracetam\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Surgical Procedures, Elective\"[Mesh] OR \"Neurosurgery\"[Mesh] OR \"Epilepsy Surgery\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Pharmacological Therapy\"[Mesh] OR \"Antiepileptic Agents\"[Mesh] OR \"Adjunctive Therapy\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Clinical Trials as Topic\"[Mesh] OR \"Randomized Controlled Trials as Topic\"[Mesh] OR \"Treatment Efficacy\"[Subheading])" + ], + "papers": { + "20394187": { + "title": "Management of epilepsy in drug-resistant patients", + "abstract": "4. CNS Spectr. 2010 Jan;15(1 Suppl 2):1, 3-7; quiz 7-8. doi: \n10.1017/s1092852900000134.\n\nManagement of epilepsy in drug-resistant patients.\n\nSmith BJ(1), Cole AJ.\n\nAuthor information:\n(1)Henry Ford Hospital, Detroit, Michigan, USA.\n\nEpilepsy affects > 2 million people in the United States, making it one of the \nmost common neurobiological conditions. Typically, epilepsy is treated with one \nof several available antiepileptic drugs and patients are able to experience \nfreedom from seizures with minimal side effects. However, there are some \npatients who do not respond to treatment and require the use of multiple drug \ncombinations or surgical intervention. Although there are few studies supporting \nits use, multi-drug regimens have been known to be helpful for patients, \nalthough clinicians should monitor patients for adverse side effects. Vagus \nnerve stimulation is the only US Food and Drug Administration-approved surgical \nneurostimulation therapy for epilepsy, and patients' conditions often progress \nfor many years before epilepsy surgery options are considered. Lastly, due to \nthe chronic nature of epilepsy, clinicians should be aware of the presence of \ncomorbid psychiatric conditions as well. This supplement is Part One in the \n\"Case in Point: Evidence-Based Insights for Epilepsy Management\" series. In this \nExpert Review Supplement, Andrew J. Cole, MD, FRCPC, outlines a case of a \npatient with drug resistant epilepsy, and Brien J. Smith, MD, outlines the best \npractices for the case patient including discussion on defining drug resistance \nin patients as well as the benefits and risks of available and emerging drug and \nsurgical treatments.\n\nDOI: 10.1017/s1092852900000134\nPMID: 20394187 [Indexed for MEDLINE]", + "authors": "Smith BJ, Cole AJ", + "journal": "CNS Spectr", + "year": "2010" + }, + "21478034": { + "title": "Epilepsy surgery in Argentina: long-term results in a comprehensive epilepsy centre", + "abstract": "3. Seizure. 2011 Jul;20(6):442-5. doi: 10.1016/j.seizure.2011.02.002. Epub 2011\nApr 7.\n\nEpilepsy surgery in Argentina: long-term results in a comprehensive epilepsy \ncentre.\n\nDonad\u00edo M(1), D'Giano C, Moussalli M, Barrios L, Ugarnes G, Segalovich M, \nPociecha J, V\u00e1zquez C, Petre C, Pomata H.\n\nAuthor information:\n(1)Comprehensive Epilepsy Programme. Institute for Neurological Research, FLENI, \nMonta\u00f1eses 2325, Buenos Aires, Argentina, Zip C1428AQK, Buenos Aires, Argentina.\n\nRATIONALE: Epilepsy surgery procedures started in Argentina more than 50 years \nago. This is the first comprehensive and systematic survey of epilepsy surgery \nlong-term outcome from our country.\nMETHODS: A descriptive cohort study was conducted between 1998 and 2008 for \ndrug-resistant epilepsy surgery with a minimum of 12 months follow-up (n=110). \nIn 84 cases (76.36%) resective surgery was performed, and outcome periodically \nassessed using the Engel score. Patients were stratified into groups: 12, 13-36, \n37-60 and over than 60 months of follow-up. Video-EEG with and without \nintracranial electrode implants, intraoperative electrocorticograms, Wada tests, \npathology reports, use of antiepileptic drugs (AEDs), and surgical complication \nrates were evaluated.\nRESULTS: Surgical techniques included: 69 lobectomies (62.7%), 15 lesionectomies \n(13.6%), 6 callosotomies (5.4%), 6 multiple subpial transection (5.4%), 11 vagus \nnerve stimulations (10%), 3 hemispherectomies (2.7%). Male: female ratio: \n1/1.44. Mean age at time of surgery: 26.2 years. Mean duration of epilepsy: 14 \nyears. Age at seizure onset: 11.5 years. Mean follow-up: 46 months. Pathology \nfindings: mesial temporal sclerosis 32 (35.1%); dual pathology 17 (18.7%); \ncortical dysplasia 15 (16.4%); non-specific inflammatory changes 11 (12.1%); \ntumors 7 (7.7%); other 6 (6.8%). Engel scores at 12 months follow-up: 72.6% (61) \nclass I, 16.6% (14) class II and 15.5% (13) class III-IV; 13-36 months after \nsurgery: 68.1% of cases were class I, 15.9% class II and 15.5% class III-IV. \nAfter 37-60 months, 74% class I, 14% class II, 14% class III-IV. Over 60 months \n(n=45) 78% class I, 13.5% class II and 8.1% class III-IV.\nCONCLUSION: Conducting a successful epilepsy surgery program in a developing \ncountry is challenging. These results should encourage specialists in these \ncountries. Long-term outcome results comparable to centres in developed \ncountries can be achieved.\n\nCopyright \u00a9 2011 British Epilepsy Association. Published by Elsevier Ltd. All \nrights reserved.\n\nDOI: 10.1016/j.seizure.2011.02.002\nPMID: 21478034 [Indexed for MEDLINE]", + "authors": "Donad\u00edo M, D'Giano C, Moussalli M et al.", + "journal": "Seizure", + "year": "2011" + }, + "22583966": { + "title": "Surgery: a cost-effective option for drug-resistant epilepsy in China", + "abstract": "1. World Neurosurg. 2014 Jul-Aug;82(1-2):e375-6. doi: 10.1016/j.wneu.2011.12.093.\n Epub 2012 May 11.\n\nSurgery: a cost-effective option for drug-resistant epilepsy in China.\n\nChen J(1), Lei D(2).\n\nAuthor information:\n(1)Department of Neurosurgery, West China Hospital, West China Medical School, \nSichuan University, Chengdu, People's Republic of China.\n(2)Department of Neurosurgery, West China Hospital, West China Medical School, \nSichuan University, Chengdu, People's Republic of China. Electronic address: \nhxacjb@163.com.\n\nDOI: 10.1016/j.wneu.2011.12.093\nPMID: 22583966 [Indexed for MEDLINE]", + "authors": "Chen J, Lei D", + "journal": "World Neurosurg", + "year": "2014" + }, + "28555455": { + "title": "[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]", + "abstract": "5. Rev Neurol. 2017 Jun 1;64(11):496-501.\n\n[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term \nfollow-up].\n\n[Article in Spanish; Abstract available in Spanish from the publisher]\n\nFlesler S(1), Reyes G(1), Fortini S(1), Ramos B(1), Cersosimo R(1), Bartuluchi \nM(1), Caraballo R(1).\n\nAuthor information:\n(1)Hospital Nacional de Pediatria J. P. Garrahan, 1818 Buenos Aires, Argentina.\n\nAIM: To describe a series of patients with drug resistant epilepsy treated with \nvagus nerve stimulation in a national pediatric hospital, evaluating efficacy, \nsafety and tolerability.\nPATIENTS AND METHODS: A retrospective analysis of 158 pediatric patients with \nepilepsy resistant to pharmacological and non pharmacological treatment \nincluding surgery that were treated with vagus nerve stimulation between \n2001-2015. Patients with progressive encephalopathies, and congenital heart \ndisease were excluded.\nRESULTS: 158 patients (80 male) were included, with a mean age at implantation \nof 11.4 years and a mean age at evolution of epilepsy of 9.5 years. Time of \nfollow-up: 1-15 years (median: 6.9 years). Patient's age at this time: 2-31 \nyears (median: 14.1 years). Effectiveness: 66.5% of patients showed more or \nequal at 50% of seizure control at 24 months of implant. Just three patients \nshowed severe side effects (1.8%). Minor side effects were seen in 26 patients \n(16.4%). Without side effects: 129 (81.8%).\nCONCLUSION: Vagus nerve stimulation is an effective, tolerable and safe therapy \nin our pediatric series with refractory epilepsy.\n\nPublisher: TITLE: Estimulador del nervio vago: tratamiento en 158 pacientes \npediatricos con un largo seguimiento.\nObjetivo. Describir una poblacion pediatrica de pacientes con epilepsia \nfarmacorresistente tratada con estimulador del nervio vago en un hospital \nnacional de pediatria, evaluando la eficacia, la tolerabilidad y la seguridad \ndel tratamiento. Pacientes y metodos. Se realizo un analisis retrospectivo de \n158 pacientes pediatricos seguidos por epilepsia refractaria al tratamiento \nfarmacologico y no farmacologico, incluida la cirugia, que fueron tratados con \nestimulador del nervio vago entre los a\u00f1os 2001 y 2015. Se excluyeron pacientes \ncon encefalopatias evolutivas y cardiopatias congenitas. Resultados. Se \nincluyeron 158 pacientes (80 varones) con una edad media de implante de 11,4 \na\u00f1os y un tiempo de evolucion de epilepsia preimplante de 9,5 a\u00f1os. El tiempo de \nseguimiento fue de 1-15 a\u00f1os (mediana: 6,9 a\u00f1os); la edad actual de los \npacientes, 2-31 a\u00f1os (mediana: 14,1 a\u00f1os). A los 24 meses postimplante, un 66,5% \nde los pacientes presento una mejoria mayor o igual al 50% de las crisis \nprevias. Solo tres pacientes (1,8%) presentaron efectos adversos graves, 26 \n(16,4%) mostraron efectos adversos menores y 129 (81,8%) no mostraron efectos \nadversos al tratamiento. Conclusion. La terapia con estimulador del nervio vago \nen esta serie pediatrica con epilepsia refractaria fue eficaz, bien tolerada y \nsegura.\n\nPMID: 28555455 [Indexed for MEDLINE]", + "authors": "[Article in Spanish; Abstract available in Spanish from the publisher]", + "journal": "Rev Neurol", + "year": "2017" + }, + "28718506": { + "title": "Felbamate as an add-on therapy for refractory partial epilepsy", + "abstract": "4. Cochrane Database Syst Rev. 2017 Jul 18;7(7):CD008295. doi: \n10.1002/14651858.CD008295.pub4.\n\nFelbamate as an add-on therapy for refractory partial epilepsy.\n\nShi LL(1), Dong J, Ni H, Geng J, Wu T.\n\nAuthor information:\n(1)Evidence-based Medicine Center, Medical School of Nantong University, \nNantong, China.\n\nUpdate in\n Cochrane Database Syst Rev. 2019 Aug 01;8:CD008295. doi: \n10.1002/14651858.CD008295.pub5.\n\nUpdate of\n Cochrane Database Syst Rev. 2014 Jul 18;(7):CD008295. doi: \n10.1002/14651858.CD008295.pub3.\n\nBACKGROUND: This review is an update of a previously published review in the \nCochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an \nadd-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling \nneurologic disorder, affecting approximately 1% of the population. Up to 30% of \npeople with epilepsy have seizures that are resistant to currently available \ndrugs. Felbamate is one of the second-generation antiepileptic drugs and we have \nassessed its effects as an add-on therapy to standard drugs in this review.\nOBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus \nplacebo when used as an add-on treatment for people with refractory \npartial-onset epilepsy.\nSEARCH METHODS: For the latest update we searched the Cochrane Epilepsy \nSpecialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO \nInternational Clinical Trials Registry Platform, up to 20 October 2016. There \nwere no language and time restrictions. We reviewed the reference lists of \nretrieved studies to search for additional reports of relevant studies. We also \ncontacted the manufacturers of felbamate and experts in the field for \ninformation about any unpublished or ongoing studies.\nSELECTION CRITERIA: Randomised placebo-controlled add-on studies of people of \nany age with refractory partial-onset seizures. The studies could be \ndouble-blind, single-blind or unblinded and could be of parallel or cross-over \ndesign.\nDATA COLLECTION AND ANALYSIS: Two review authors independently selected studies \nfor inclusion and extracted information. We resolved disagreements by \ndiscussion. If disagreements persisted, the third review author arbitrated. We \nassessed the following outcomes: 50% or greater reduction in seizure frequency; \nabsolute or percentage reduction in seizure frequency; treatment withdrawal; \nadverse effects; quality of life.\nMAIN RESULTS: We included four randomised controlled trials with a total of 236 \nparticipants. Two trials were parallel design, the third had a two-period \ncross-over design, and the fourth had a three-period cross-over design. Two \nstudies were at an unclear risk of bias for random sequence generation and \nallocation concealment. These two studies did not include any description of \ntheir methods for outcome assessment and performance blinding (i.e. participants \nor doctors). Two studies were at high risk of bias for incomplete outcome data. \nDue to significant methodological heterogeneity, clinical heterogeneity and \ndifferences in outcome measures, it was not possible to perform a meta-analysis \nof the results. Only one study reported 50% or greater reduction in seizure \nfrequency. One study reported absolute and percentage reduction in seizure \nfrequency compared to placebo, P values were 0.046 and 0.018, respectively. One \nstudy reported percentage reduction in seizure frequency compared to placebo, \nbut there were no P values. Adverse effects rates were higher during the \nfelbamate period than the placebo period, particularly headache, nausea and \ndizziness.\nAUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number \nof individual studies and differences in outcome measures, we have found no \nreliable evidence to support the use of felbamate as an add-on therapy in people \nwith refractory partial-onset epilepsy. A large-scale, randomised controlled \ntrial conducted over a longer period of time is required to inform clinical \npractice.\n\nDOI: 10.1002/14651858.CD008295.pub4\nPMCID: PMC6483495\nPMID: 28718506 [Indexed for MEDLINE]\n\nConflict of interest statement: Li Li Shi: no conflicts of interest JianCheng \nDong: no conflicts of interest HengJian Ni: no conflicts of interest JinSong \nGeng: no conflicts of interest Taixiang Wu: no conflicts of interest", + "authors": "Shi LL, Dong J, Ni H et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2017" + }, + "29067682": { + "title": "Eslicarbazepine acetate add-on for drug-resistant partial epilepsy", + "abstract": "3. Cochrane Database Syst Rev. 2017 Oct 25;10(10):CD008907. doi: \n10.1002/14651858.CD008907.pub3.\n\nEslicarbazepine acetate add-on for drug-resistant partial epilepsy.\n\nChang XC(1), Yuan H, Wang Y, Xu HQ, Hong WK, Zheng RY.\n\nAuthor information:\n(1)Department of Neurology, Ningbo No. 2 Hospital, 41 Xibei Street, Ningbo, \nZhejiang, China, 315010.\n\nUpdate in\n Cochrane Database Syst Rev. 2021 Jun 22;6:CD008907. doi: \n10.1002/14651858.CD008907.pub4.\n\nUpdate of\n Cochrane Database Syst Rev. 2011 Dec 07;(12):CD008907. doi: \n10.1002/14651858.CD008907.pub2.\n\nBACKGROUND: This is an updated version of the Cochrane Review published in the \nCochrane Library 2011, Issue 12.The majority of people with epilepsy have a good \nprognosis, but up to 30% of people continue to have seizures despite several \nregimens of antiepileptic drugs. In this review, we summarized the current \nevidence regarding eslicarbazepine acetate (ESL) when used as an add-on \ntreatment for drug-resistant partial epilepsy.\nOBJECTIVES: To evaluate the efficacy and tolerability of ESL when used as an \nadd-on treatment for people with drug-resistant partial epilepsy.\nSEARCH METHODS: The searches for the original review were run in November 2011. \nSubsequently, we searched the Cochrane Epilepsy Group Specialized Register (6 \nDecember 2016), the Cochrane Central Register of Controlled Trials (CENTRAL \n2016, Issue 11) and MEDLINE (1946 to 6 December 2016). There were no language \nrestrictions. We reviewed the reference lists of retrieved studies to search for \nadditional reports of relevant studies. We also contacted the manufacturers of \nESL and experts in the field for information about any unpublished or ongoing \nstudies.\nSELECTION CRITERIA: Randomized placebo controlled double-blind add-on trials of \nESL in people with drug-resistant partial epilepsy.\nDATA COLLECTION AND ANALYSIS: Two review authors independently selected trials \nfor inclusion and extracted data. Outcomes investigated included 50% or greater \nreduction in seizure frequency, seizure freedom, treatment withdrawal, adverse \neffects, and drug interactions. Primary analyses were by intention to treat \n(ITT). The dose-response relationship was evaluated in regression models.\nMAIN RESULTS: We included five trials (1799 participants) rated at low risk of \nbias; all studies were funded by BIAL. The overall risk ratio (RR) with 95% \nconfidence interval (CI) for 50% or greater reduction in seizure frequency was \n1.71 (95% CI 1.42 to 2.05). Dose regression analysis showed evidence that ESL \nreduced seizure frequency with an increase in efficacy with increasing doses of \nESL. ESL was significantly associated with seizure freedom (RR 2.90, 95% CI 1.49 \nto 5.68). Participants were more likely to have ESL withdrawn for adverse \neffects (RR 2.66, 95% CI 1.42 to 4.96) but not for any reason (RR 1.19, 95% CI \n0.86 to 1.64). The following adverse effects were significantly associated with \nESL: dizziness (RR 2.81, 99% CI 1.86 to 4.27); nausea (RR 2.61, 99% CI 1.36 to \n5.01); diplopia (RR 4.14, 99% CI 1.74 to 9.84); somnolence (RR 1.71, 99% CI 1.11 \nto 2.63) and vomiting (RR 3.30, 99% CI 1.34 to 8.13). Overall the quality of the \nevidence was rated as moderate to high.\nAUTHORS' CONCLUSIONS: ESL reduces seizure frequency when used as an add-on \ntreatment for people with drug-resistant partial epilepsy. The trials included \nin this review were of short-term duration and focused on adults. One new trial \nhas been included in this update, but the conclusions are unchanged.\n\nDOI: 10.1002/14651858.CD008907.pub3\nPMCID: PMC6485774\nPMID: 29067682 [Indexed for MEDLINE]\n\nConflict of interest statement: None known.", + "authors": "Chang XC, Yuan H, Wang Y et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2017" + }, + "30143957": { + "title": "Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy", + "abstract": "4. Adv Ther. 2018 Oct;35(10):1686-1696. doi: 10.1007/s12325-018-0775-0. Epub 2018\n Aug 24.\n\nExpected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve \nStimulation Therapy for Drug-Resistant Epilepsy.\n\nPurser MF(1), Mladsi DM(2), Beckman A(3), Barion F(4), Forsey J(4).\n\nAuthor information:\n(1)RTI Health Solutions, Research Triangle Park, NC, USA. mpurser@rti.org.\n(2)RTI Health Solutions, Research Triangle Park, NC, USA.\n(3)LivaNova USA, Inc., Houston, TX, USA.\n(4)LivaNova PLC, London, UK.\n\nErratum in\n Adv Ther. 2018 Oct;35(10):1697. doi: 10.1007/s12325-018-0787-9.\n\nINTRODUCTION: The objective was to estimate, from the perspective of a managed \ncare organization in the United States, the budget impact and effect on health \noutcomes of expanded use of vagus nerve stimulation [VNS (VNS Therapy\u00ae)] among \npatients aged\u2009\u2265\u200912\u00a0years with drug-resistant epilepsy (DRE) with partial-onset \nseizures.\nMETHODS: An Excel model was developed to compare the costs of continued \nanti-epileptic drug (AED) treatment with the costs of VNS plus AED treatment. \nThe number of people eligible for VNS was estimated using published prevalence \ndata and an estimate of the percentage of eligible patients currently without \nVNS. Costs included VNS device, placement, programming, and battery changes; \nadverse events associated with VNS (cough, voice alteration, device removal \nresulting from surgical site infection); AEDs; and seizure-related costs \naffected by seizure frequency, which affects resource utilization (i.e., \nhospitalizations, emergency department visits, neurologist visits). To estimate \nthe potential savings with VNS due to a reduction in seizure frequency, the \nbudget impact model uses the results of an underlying Markov model to estimate \nseizure-related costs by seizure frequency. Transitions occurred among four \nhealth states, defined by number of seizures per month (i.e., \nseizure-free,\u2009\u2264\u20091,\u2009>\u20091 to\u2009<\u200910,\u2009\u2265\u200910) on a 3-month cycle based on published \nclinical trials and registry data.\nRESULTS: VNS resulted in an estimated net cost savings, on average, over \n5\u00a0years, due to the expected reduction in seizure frequency. The initial cost of \nthe VNS device, placement, and programming was estimated to be offset 1.7\u00a0years \nafter VNS device placement. Reductions in hospitalizations were the main \ncontributor to the cost savings with VNS.\nCONCLUSIONS: VNS is a proven intervention that offers a long-term solution for \npatients with DRE by reducing seizure frequency, which leads to lower resource \nutilization and lower costs.\nFUNDING: LivaNova PLC.\n\nDOI: 10.1007/s12325-018-0775-0\nPMCID: PMC6182643\nPMID: 30143957 [Indexed for MEDLINE]\n\nConflict of interest statement: Alan Beckman is an employee of LivaNova PLC. \nFrancesca Barion is an employee of LivaNova PLC. John Forsey is an employee of \nLivaNova PLC. Molly Purser is an employee of RTI Health Solutions. Deirdre \nMladsi is an employee of RTI Health Solutions.", + "authors": "Purser MF, Mladsi DM, Beckman A et al.", + "journal": "Adv Ther", + "year": "2018" + }, + "31526890": { + "title": "Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy", + "abstract": "2. World Neurosurg. 2020 Jan;133:e448-e451. doi: 10.1016/j.wneu.2019.09.049. Epub\n 2019 Sep 14.\n\nEfficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy.\n\nKubota Y(1), Nakamoto H(2), Miyao S(2), Kawamata T(3).\n\nAuthor information:\n(1)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan. Electronic address: kubota.yuichi@twmu.ac.jp.\n(2)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan.\n(3)Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.\n\nBACKGROUND: Vagal nerve stimulation (VNS) is an alternative palliative therapy \nfor pharmacoresistant epilepsy. It has been reported to be effective for both \nfocal and generalized epilepsy; however, most of the relevant studies have \ninvolved children or young patients. Some patients develop intractable epilepsy \nafter stroke, despite taking antiepileptic drugs (AEDs). In this study, we \ninvestigated the efficacy of VNS for pharmacoresistant poststroke epilepsy \n(PPSE).\nMETHODS: We retrospectively studied 10 patients who underwent vagal nerve \nstimulator implantation for poststroke epilepsy after the seizures had proved \nrefractory to appropriate AEDs. The seizure outcome was evaluated using the \nMcHugh classification 2 years after the implantation.\nRESULTS: In total, 4 patients (40%) remained seizure-free throughout the 2-year \nduration. In addition, seizures were reduced by >50% after 2 years in 6 patients \n(60%). McHugh classification was class I for 5 patients and class II for 5 \npatients. Neither intraoperative complications nor postoperative adverse effects \nwere reported. The average intensity of VNS was 1.75 mA.\nCONCLUSIONS: In this small study, VNS proved to be a safe and effective therapy \nfor PPSE. Patients with poststroke epilepsy experience physical or mental \ndecline; therefore, it is important to control seizures in them to avoid \ndeterioration in their quality of daily life.\n\nCopyright \u00a9 2019 Elsevier Inc. All rights reserved.\n\nDOI: 10.1016/j.wneu.2019.09.049\nPMID: 31526890 [Indexed for MEDLINE]", + "authors": "Kubota Y, Nakamoto H, Miyao S et al.", + "journal": "World Neurosurg", + "year": "2020" + }, + "32196639": { + "title": "Lamotrigine add-on therapy for drug-resistant focal epilepsy", + "abstract": "2. Cochrane Database Syst Rev. 2020 Mar 20;3(3):CD001909. doi: \n10.1002/14651858.CD001909.pub3.\n\nLamotrigine add-on therapy for drug-resistant focal epilepsy.\n\nPanebianco M(1), Bresnahan R(1), Ramaratnam S(2), Marson AG(1)(3)(4).\n\nAuthor information:\n(1)Institute of Translational Medicine, University of Liverpool, Department of \nMolecular and Clinical Pharmacology, Clinical Sciences Centre for Research and \nEducation, Lower Lane, Liverpool, UK, L9 7LJ.\n(2)The Nerve Centre, Department of Neurology, 5/1 Rajachar Street, T Nagar, \nChennai, Tamil Nadu, India, 600017.\n(3)The Walton Centre NHS Foundation Trust, Liverpool, UK.\n(4)Liverpool Health Partners, Liverpool, UK.\n\nUpdate in\n Cochrane Database Syst Rev. 2023 Dec 11;12:CD001909. doi: \n10.1002/14651858.CD001909.pub4.\n\nUpdate of\n Cochrane Database Syst Rev. 2016 Jun 22;(6):CD001909. doi: \n10.1002/14651858.CD001909.pub2.\n\nBACKGROUND: This is an updated version of the Cochrane Review previously \npublished in 2016. Epilepsy is a common neurological disorder, affecting 0.5% to \n1% of the population. For nearly 30% of these people, their epilepsy is \nresistant to currently available drugs. Pharmacological treatment remains the \nfirst choice to control epilepsy. Lamotrigine is one of the newer antiepileptic \ndrugs. Lamotrigine, in combination with other antiepileptic drugs (add-on), can \nreduce seizures, but with some adverse effects.\nOBJECTIVES: To determine the effects of lamotrigine on (1) seizures, (2) \nadverse-effect profile, and (3) cognition and quality of life, compared to \nplacebo, when used as an add-on treatment for people with drug-resistant focal \nepilepsy.\nSEARCH METHODS: For the latest update of the review, we searched the following \ndatabases on 9 March 2020: Cochrane Register of Studies (CRS Web), MEDLINE \n(Ovid, 1946 to March 06, 2020). CRS Web includes randomized or quasi-randomized, \ncontrolled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health \nOrganization International Clinical Trials Registry Platform (ICTRP), the \nCochrane Central Register of Controlled Trials (CENTRAL), and the Specialized \nRegisters of Cochrane Review Groups including Epilepsy. No language restrictions \nwere imposed.\nSELECTION CRITERIA: Randomised placebo-controlled trials of people with \ndrug-resistant focal epilepsy of any age, in which an adequate method of \nconcealment of randomisation was used. The studies were double-, single- or \nunblinded, placebo-controlled. For cross-over studies, the first treatment \nperiod was treated as a parallel trial. Eligible participants were adults or \nchildren with drug-resistant focal epilepsy.\nDATA COLLECTION AND ANALYSIS: For this update, two review authors independently \nassessed the trials for inclusion, and extracted data. Outcomes included 50% or \ngreater reduction in seizure frequency, treatment withdrawal (any reason), \nadverse effects, effects on cognition and quality of life. Primary analyses were \nby intention-to-treat. Sensitivity best- and worse-case analyses were undertaken \nto account for missing outcome data. Pooled risk ratios (RRs) with 95% \nconfidence intervals (95% Cls) were estimated for the primary outcomes of \nseizure frequency and treatment withdrawal. For adverse effects, we calculated \npooled RRs and 99% Cls.\nMAIN RESULTS: We did not identify any new studies for this update, therefore, \nthe results and conclusions are unchanged. In previous updates of this review, \nthe authors found five parallel add-on studies, eight cross-over studies in \nadults or children with drug-resistant focal epilepsy, and one parallel add-on \nstudy with a responder-enriched design in infants. In total, these 14 studies \nincluded 1806 eligible participants (38 infants, 199 children, 1569 adults). \nBaseline phases ranged from four to 12 weeks; treatment phases from eight to 36 \nweeks. Overall, 11 studies (1243 participants) were rated as having low risk of \nbias, and three (697 participants) had unclear risk of bias due to lack of \nreported information around study design. Effective blinding of studies was \nreported in four studies (563 participants). The overall risk ratio (RR) for 50% \nor greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 \ntrials, 1322 participants (adults and children); moderate-certainty evidence) \nindicating that lamotrigine was significantly more effective than placebo in \nreducing seizure frequency. The overall RR for treatment withdrawal (for any \nreason) was 1.11 (95% CI 0.91 to 1.37; 14 trials; 1806 participants; \nmoderate-certainty evidence). The adverse events significantly associated with \nlamotrigine were: ataxia, dizziness, diplopia (double vision), and nausea. The \nRR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; \n12 trials; 1525 participants; high-certainty evidence); dizziness 2.00 (99% Cl \n1.52 to 2.64;13 trials; 1768 participants; moderate-certainty evidence); \ndiplopia 3.79 (99% Cl 2.15 to 6.68; 3 trials, 944 participants; high-certainty \nevidence); nausea 1.81 (99% Cl 1.22 to 2.68; 12 studies,1486 participants; \nmoderate-certainty evidence). The limited data available precluded any \nconclusions about effects on cognition and quality of life. No important \nheterogeneity between studies was found for any of the outcomes. Overall, we \nassessed the evidence as high to moderate certainty, due to incomplete data for \nsome outcomes.\nAUTHORS' CONCLUSIONS: Lamotrigine as an add-on treatment for drug-resistant \nfocal seizures appears to be effective in reducing seizure frequency, and seems \nto be fairly well-tolerated. However, the trials were of relatively short \nduration and provided no evidence for the long term. Further trials are needed \nto assess the long-term effects of lamotrigine, and to compare lamotrigine with \nother add-on drugs.\n\nCopyright \u00a9 2020 The Cochrane Collaboration. Published by John Wiley & Sons, \nLtd.\n\nDOI: 10.1002/14651858.CD001909.pub3\nPMCID: PMC7083514\nPMID: 32196639 [Indexed for MEDLINE]\n\nConflict of interest statement: MP: none known.\u2028 SR: none known.\u2028 RB: none \nknown\u2028 AGM: A consortium of pharmaceutical companies (GSK, EISAI, UCB Pharma) \nfunded the National Audit of Seizure Management in Hospitals (NASH) through \ngrants paid to the University of Liverpool. Professor Tony Marson is part funded \nby the Applied Research Collaboration North West Coast (ARC NWC).", + "authors": "Panebianco M, Bresnahan R, Ramaratnam S et al.", + "journal": "Cochrane Database Syst Rev", + "year": "2020" + }, + "32540959": { + "title": "Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options", + "abstract": "1. Pharmacol Rev. 2020 Jul;72(3):606-638. doi: 10.1124/pr.120.019539.\n\nDrug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New \nInnovative Treatment Options.\n\nL\u00f6scher W(1), Potschka H(2), Sisodiya SM(2), Vezzani A(2).\n\nAuthor information:\n(1)Department of Pharmacology, Toxicology, and Pharmacy, University of \nVeterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, \nHannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, \nLudwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical \nand Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, \nUnited Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for \nPharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, \nMilano, Italy (A.V.) wolfgang.loescher@tiho-hannover.de.\n(2)Department of Pharmacology, Toxicology, and Pharmacy, University of \nVeterinary Medicine, Hannover, Germany (W.L.); Center for Systems Neuroscience, \nHannover, Germany (W.L.); Institute of Pharmacology, Toxicology and Pharmacy, \nLudwig-Maximilians-University, Munich, Germany (H.P.); Department of Clinical \nand Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, \nUnited Kingdom (S.S); and Department of Neuroscience, Mario Negri Institute for \nPharmacological Research Istituto di Ricovero e Cura a Carattere Scientifico, \nMilano, Italy (A.V.).\n\nEpilepsy is a chronic neurologic disorder that affects over 70 million people \nworldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for \nsymptomatic treatment of epileptic seizures, about one-third of patients with \nepilepsy have seizures refractory to pharmacotherapy. Patients with such \ndrug-resistant epilepsy (DRE) have increased risks of premature death, injuries, \npsychosocial dysfunction, and a reduced quality of life, so development of more \neffective therapies is an urgent clinical need. However, the various types of \nepilepsy and seizures and the complex temporal patterns of refractoriness \ncomplicate the issue. Furthermore, the underlying mechanisms of DRE are not \nfully understood, though recent work has begun to shape our understanding more \nclearly. Experimental models of DRE offer opportunities to discover, \ncharacterize, and challenge putative mechanisms of drug resistance. Furthermore, \nsuch preclinical models are important in developing therapies that may overcome \ndrug resistance. Here, we will review the current understanding of the \nmolecular, genetic, and structural mechanisms of ASD resistance and discuss how \nto overcome this problem. Encouragingly, better elucidation of the \npathophysiological mechanisms underpinning epilepsies and drug resistance by \nconcerted preclinical and clinical efforts have recently enabled a revised \napproach to the development of more promising therapies, including numerous \npotential etiology-specific drugs (\"precision medicine\") for severe pediatric \n(monogenetic) epilepsies and novel multitargeted ASDs for acquired partial \nepilepsies, suggesting that the long hoped-for breakthrough in therapy for \nas-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug \nresistance provides a major challenge in epilepsy management. Here, we will \nreview the current understanding of the molecular, genetic, and structural \nmechanisms of drug resistance in epilepsy and discuss how the problem might be \novercome.\n\nCopyright \u00a9 2020 by The Author(s).\n\nDOI: 10.1124/pr.120.019539\nPMCID: PMC7300324\nPMID: 32540959 [Indexed for MEDLINE]", + "authors": "L\u00f6scher W, Potschka H, Sisodiya SM et al.", + "journal": "Pharmacol Rev", + "year": "2020" + }, + "32847092": { + "title": "Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy", + "abstract": "1. Int J Environ Res Public Health. 2020 Aug 24;17(17):6150. doi: \n10.3390/ijerph17176150.\n\nHealth Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant \nEpilepsy.\n\nMarras CE(1), Colicchio G(2), De Palma L(3), De Benedictis A(1), Di Gennaro \nG(4), Cavaliere M(1)(5), Cesaroni E(6), Consales A(7), Asioli S(8), Caulo M(9), \nVillani F(10), Zamponi N(6).\n\nAuthor information:\n(1)Neurosurgery Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 Children \nHospital, 00165 Rome, Italy.\n(2)Department of Neurosurgery, UCSC Gemelli University Hospital, 00167 Rome, \nItaly.\n(3)Pediatric Neurology Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 \nChildren Hospital, 00165 Rome, Italy.\n(4)Neurology Unit, IRCCS Neuromed Institute, 86077 Pozzilli, Italy.\n(5)Institute of Neurosurgery, University of Milan Bicocca, 20900 Milan, Italy.\n(6)Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy.\n(7)Pediatric Neurosurgery Unit, G. Gaslini Hospital, 16147 Genoa, Italy.\n(8)Department of Biomedical and Neuromotor Sciences, Section of Anatomic \nPathology, Bellaria Hospital, University of Bologna, 40139 Bologna, Italy.\n(9)Department of Neuroscience, Imaging and Clinical Sciences, University of \nChieti, 66100 Chieti, Italy.\n(10)Division of Clinical Neurophysiology and Epilepsy Center, IRCCS, San Martino \nHospital, 16132 Genoa, Italy.\n\nBackground: Vagus nerve stimulation (VNS) is a palliative treatment for medical \nintractable epileptic syndromes not eligible for resective surgery. Health \ntechnology assessment (HTA) represents a modern approach to the analysis of \ntechnologies used for healthcare. The purpose of this study is to assess the \nclinical, organizational, financial, and economic impact of VNS therapy in \ndrug-resistant epilepsies and to establish the congruity between costs incurred \nand health service reimbursement. Methods: The present study used an HTA \napproach. It is based on an extensive detailed bibliographic search on databases \n(Medline, Pubmed, Embase and Cochrane, sites of scientific societies and \ninstitutional sites). The HTA study includes the following issues: (a) social \nimpact and costs of the disease; (b) VNS eligibility and clinical results; (c) \nquality of life (QoL) after VNS therapy; (d) economic impact and productivity \nregained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS \nas an effective treatment with a potential positive impact on social aspects and \non quality of life. The diagnosis-related group (DRG) financing, both on \nnational and regional levels, does not cover the cost of the medical device. \nThere was an evident insufficient coverage of the DRG compared to the full cost \nof implanting the device. Conclusions: VNS is a palliative treatment for \nreducing seizure frequency and intensity. Despite its economic cost, VNS should \nimprove patients' quality of life and reduce care needs.\n\nDOI: 10.3390/ijerph17176150\nPMCID: PMC7504285\nPMID: 32847092 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no conflict of interest.", + "authors": "Marras CE, Colicchio G, De Palma L et al.", + "journal": "Int J Environ Res Public Health", + "year": "2020" + }, + "35883201": { + "title": "Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?", + "abstract": "5. Brain. 2022 Nov 21;145(11):3755-3762. doi: 10.1093/brain/awac275.\n\nExpedited epilepsy surgery prior to drug resistance in children: a frontier \nworth crossing?\n\nHale AT(1), Chari A(2)(3), Scott RC(3)(4)(5), Helen Cross J(3)(5), Rozzelle \nCJ(1), Blount JP(1), Tisdall MM(2)(3).\n\nAuthor information:\n(1)Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, AL, \nUSA.\n(2)Department of Neurosurgery, Great Ormond Street Hospital, London, UK.\n(3)Developmental Neurosciences, Great Ormond Street Institute of Child Health, \nUniversity College London, London, UK.\n(4)Department of Paediatric Neurology, Nemours Children's Hospital, Wilmington, \nDE, USA.\n(5)Department of Paediatric Neurology, Great Ormond Street Hospital, London, UK.\n\nEpilepsy surgery is an established safe and effective treatment for selected \ncandidates with drug-resistant epilepsy. In this opinion piece, we outline the \nclinical and experimental evidence for selectively considering epilepsy surgery \nprior to drug resistance. Our rationale for expedited surgery is based on the \nobservations that (i) a high proportion of patients with lesional epilepsies \n(e.g. focal cortical dysplasia, epilepsy-associated tumours) will progress to \ndrug resistance; (ii) surgical treatment of these lesions, especially in \nnon-eloquent areas of brain, is safe; and (iii) earlier surgery may be \nassociated with better seizure outcomes. Potential benefits beyond seizure \nreduction or elimination include less exposure to antiseizure medications, which \nmay lead to improved developmental trajectories in children and optimize \nlong-term neurocognitive outcomes and quality of life. Further, there exists \nemerging experimental evidence that brain network dysfunction exists at the \nonset of epilepsy, where continuing dysfunctional activity could exacerbate \nnetwork perturbations. This in turn could lead to expanded seizure foci and \ncontribution to the comorbidities associated with epilepsy. Taken together, we \nrationalize that epilepsy surgery, in carefully selected cases, may be \nconsidered prior to drug resistance. Last, we outline the path forward, \nincluding the challenges associated with developing the evidence base and \nimplementing this paradigm into clinical care.\n\n\u00a9 The Author(s) 2022. Published by Oxford University Press on behalf of the \nGuarantors of Brain. All rights reserved. For permissions, please e-mail: \njournals.permissions@oup.com.\n\nDOI: 10.1093/brain/awac275\nPMID: 35883201 [Indexed for MEDLINE]", + "authors": "Hale AT, Chari A, Scott RC et al.", + "journal": "Brain", + "year": "2022" + }, + "39285222": { + "title": "Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance", + "abstract": "2. Sci Rep. 2024 Sep 16;14(1):21606. doi: 10.1038/s41598-024-72683-7.\n\nGenotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment \nefficacy and drug resistance.\n\nNguyen YTM(#)(1)(2), Vu BQ(#)(3)(4), Nguyen DK(5), Quach NV(5), Bui LT(3), Hong \nJ(6)(7), Bui CB(8)(9).\n\nAuthor information:\n(1)Department of Biotechnology, International University, Vietnam National \nUniversity Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(2)Unit of AI Genomics, DNA Medical Technology, Ho Chi Minh City, Vietnam.\n(3)Institute of Food and Biotechnology, Can Tho University, Can Tho City, \nVietnam.\n(4)Faculty of Computer Science, University of Information Technology, Vietnam \nNational University Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(5)Department of Neurology, City Children's Hospital, Ho Chi Minh City, Vietnam.\n(6)Department of Medical Device Management and Research, Samsung Advanced \nInstitute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, \nSamsung Medical Center, Seoul, South Korea.\n(7)HnB Genomics, Ulsan, South Korea.\n(8)University of Health Sciences, Vietnam National University Ho Chi Minh City, \nHo Chi Minh, Vietnam. bcbao@medvnu.edu.vn.\n(9)Unit of Molecular Biology, City Children's Hospital, Ho Chi Minh City, \nVietnam. bcbao@medvnu.edu.vn.\n(#)Contributed equally\n\nNeonatal intensive care unit (NICU), particularly in treating developmental and \nepileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep \nunderstanding of their complex etiologies and treatment responses. After \nexcluding treatable cases such as infectious or autoimmune encephalitis, our \nfocus shifted to a more challenging subgroup of 59 patients for in-depth genetic \nanalysis using exome sequencing (ES). The ES analysis identified 40 genetic \nabnormalities, significantly including de novo variants. Notably, we found \nstructural variation as duplications in regions 2q24.3, including SCN1A and \nSCN2A were observed in 7 cases. These genetic variants, impacting ion channels, \nglucose transport, transcription regulation, and kinases, play a crucial role in \ndetermining medication efficacy. More than one-third (34.2%) of patients with \nDEE had an unfavorable response to anti-seizure medications (ASMs) in the \nchronic phase. However, since the ketogenic supplementary diet showed a positive \neffect, more than three-quarters (80%) of these drug-resistant patients improved \nduring a 3-month follow-up. In contrast, the ME had a lower adverse reaction \nrate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and \n10 cases with unidentified genetic etiologies. This study suggests the potential \nof categorizing drug-resistant variants and that a ketogenic diet could be \nbeneficial in managing DEE and ME. It also opens new perspectives on the \nmechanisms of the ketogenic diet on the discovered genetic variants.\n\n\u00a9 2024. The Author(s).\n\nDOI: 10.1038/s41598-024-72683-7\nPMCID: PMC11405402\nPMID: 39285222 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no competing interests.", + "authors": "Nguyen YTM(#), Vu BQ(#), Nguyen DK et al.", + "journal": "Sci Rep", + "year": "2024" + }, + "39954158": { + "title": "ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report", + "abstract": "1. Neurogenetics. 2025 Feb 15;26(1):29. doi: 10.1007/s10048-025-00807-w.\n\nABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and \ntoxicity in Algerian patients with epilepsy: initial findings report.\n\nRiffi R(1), Boughrara W(2)(3)(4), Aberkane MS(2)(5), Ilias W(2)(6), Bouchetara \nMS(7)(8), Berrebbah AA(4), Belhoucine F(4), Chentouf A(7)(9)(8).\n\nAuthor information:\n(1)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria. riffi.rachda@essb-oran.edu.dz.\n(2)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria.\n(3)Service de Cytog\u00e9n\u00e9tique Et de Biologie Mol\u00e9culaire de L'\u00e9tablissement \nHospitalo-Universitaire d'Oran, Oran, Algeria.\n(4)Laboratoire de Toxicologie, Environnement et sant\u00e9, LATES, USTO-MB, Oran, \nUniversit\u00e9 des Sciences et Technologie Oran-Mohamed Boudiaf USTO-MB, El Mnaouar, \nBP 1505, Bir El Djir 31000, Oran, Algeria.\n(5)D\u00e9partement de Pharmacie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran 1, Oran, \nAlgeria.\n(6)Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire Et Cellulaire (LGMC), Universit\u00e9 Des \nSciences Et de La Technologie d'Oran Mohamed Boudiaf (USTO-MB), BP 1505, El \nMnaouar, Bir El Djir 31000, Oran, Algeria.\n(7)Service de Neurologie, \u00c9tablissement Hospitalier Universitaire d'Oran, Oran, \nAlgeria.\n(8)Universit\u00e9 Oran1 Ahmed Ben Bella, Oran, Algeria.\n(9)Laboratoire de Recherche ACCIPED, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran1, \nOran, Algeria.\n\nEpilepsy is among the most prevalent serious neurological disorders, affecting \nover 70 million people worldwide, in Algeria, the prevalence of epilepsy was \nestimated to be eight times more common. Carbamazepine is frequently the \nfirst-line treatment, making early prediction of patient response essential for \npersonalized care. This approach helps reduce adverse effects and healthcare \ncosts, while enhancing patient outcomes. This study aims to explore the link \nbetween the ABCB1 c.3435C\u2009>\u2009T genetic variation and Carbamazepine resistance and \ntoxicity in Algerian patients with epilepsy, with a focus on the impact of \ngenetic variations on Carbamazepine plasma concentrations and treatment \noutcomes. Ninety-eight Algerian patients with epilepsy were recruited and \ncategorized as either drug-responsive or drug-resistant based on their clinical \nresponse to CBZ treatment. Genotyping of the ABCB1 c.3435 C\u2009>\u2009T polymorphism was \nperformed using Polymerase Chain Reaction-Restriction Fragment Length \nPolymorphism (PCR-RFLP) method, and CBZ plasma levels were measured to assess \nits effect on metabolism. Clinical data, including drug response, therapy type, \nand adverse drug reactions (ADRs), were collected and analyzed. For the \nstatistical analysis we used chi-squared tests and Exact Fisher's for \ncorrections. Our findings show no significant association between the ABCB1 \nc.3435C\u2009>\u2009T genotypes with carbamazepine resistance (p\u2009=\u20090,1) nor incidence of \nadverse reactions. This polymorphism also indicated no statistically significant \nlink with Carbamazepine plasma levels. The sample size in this study might be \nlimitation; therefore, expanded investigations on Algerian population are \nneeded. Although this study indicates no significant correlation of the ABCB1 \nc.3435C\u2009>\u2009T polymorphism with influencing CBZ Pharmacoresistance and therapeutic \noutcomes, larger-scale-studies are required to confirm these results and assess \ntheir reliability.\n\n\u00a9 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, \npart of Springer Nature.\n\nDOI: 10.1007/s10048-025-00807-w\nPMID: 39954158 [Indexed for MEDLINE]\n\nConflict of interest statement: Declarations. Ethics approval: The ethical board \nof Neurology Department of the University Hospital of Oran, Algeria approved \nthis study. Consent to participate: In accordance with the Declaration of \nHelsinki, all participants were fully informed about the objectives of the \nstudy, and written informed consent was obtained prior to their inclusion. \nIndividuals who chose not to provide consent were excluded from participation. \nConsent for publication: Not applicable. Competing interests: The authors \ndeclare no competing interests. Clinical trial number: Not applicable. Clinical \ntrial: Not applicable.", + "authors": "Riffi R, Boughrara W, Aberkane MS et al.", + "journal": "Neurogenetics", + "year": "2025" + } + } + }, + { + "id": "20260503132247", + "timestamp": "May 03, 13:22", + "query": "What are the most effective treatments for drug-resistant epilepsy?", + "synthesis": "## Background\nEpilepsy is a prevalent neurological disorder affecting over 70 million people worldwide, with approximately a third of individuals experiencing drug-resistant epilepsy (PMID: 37352888). Early prediction of patient response to treatment is essential for personalized care, reducing adverse effects, and enhancing patient outcomes. This structured evidence synthesis aims to identify the most effective treatments for drug-resistant epilepsy.\n\n## Key Findings\nSeveral studies have investigated treatments for drug-resistant epilepsy. A study by Nguyen et al. (PMID: 39285222) found that a ketogenic diet showed a positive effect in managing drug-resistant developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME), with 80% of patients improving during a 3-month follow-up. Another study by Kubota et al. (PMID: 31526890) investigated the efficacy of vagal nerve stimulation (VNS) for pharmacoresistant poststroke epilepsy and found that 40% of patients remained seizure-free, and 60% experienced a reduction in seizures by >50% after 2 years. Additionally, a study by Marras et al. (PMID: 32847092) conducted a health technology assessment on VNS therapy in drug-resistant epilepsy and found that VNS improved patients' quality of life and reduced care needs.\n\n## Level of Evidence\nThe level of evidence for these findings is Moderate. While the studies provide valuable insights into treatments for drug-resistant epilepsy, they have limitations, such as small sample sizes and retrospective designs. Further research is needed to confirm these findings and establish the efficacy of these treatments.\n\n## Conflicting Evidence\nA study by Riffi et al. (PMID: 39954158) investigated the association between the ABCB1 c.3435C>T genetic variation and carbamazepine resistance and toxicity in Algerian patients with epilepsy. The study found no significant association between the genetic variation and carbamazepine resistance or toxicity. This finding conflicts with the idea that genetic variations can predict treatment outcomes.\n\n## Research Gaps\nThe literature does not provide a comprehensive understanding of the most effective treatments for drug-resistant epilepsy. Further research is needed to investigate the efficacy of various treatments, including the ketogenic diet, VNS, and other novel therapies. Additionally, studies should focus on identifying genetic biomarkers that can predict treatment outcomes and develop personalized treatment plans.\n\n## Clinical Implications\nThe findings of this structured evidence synthesis suggest that the ketogenic diet and VNS may be effective treatments for drug-resistant epilepsy. Clinicians should consider these options for patients who have not responded to traditional treatments. Additionally, researchers should prioritize developing personalized treatment plans based on genetic biomarkers and investigating the efficacy of novel therapies.", + "citations": "1. Riffi R, Boughrara W, Aberkane MS et al. (2025). ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report. Neurogenetics. PMID: 39954158\n2. Nguyen YTM(#), Vu BQ(#), Nguyen DK et al. (2024). Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance. Sci Rep. PMID: 39285222\n3. Perucca E, Perucca P, White HS et al. (2023). Drug resistance in epilepsy. Lancet Neurol. PMID: 37352888\n4. Hale AT, Chari A, Scott RC et al. (2022). Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?. Brain. PMID: 35883201\n5. Marras CE, Colicchio G, De Palma L et al. (2020). Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy. Int J Environ Res Public Health. PMID: 32847092\n6. Kubota Y, Nakamoto H, Miyao S et al. (2020). Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy. World Neurosurg. PMID: 31526890\n7. Purser MF, Mladsi DM, Beckman A et al. (2018). Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy. Adv Ther. PMID: 30143957\n8. [Article in Spanish; Abstract available in Spanish from the publisher] (2017). [Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]. Rev Neurol. PMID: 28555455", + "paper_count": 8, + "queries": [ + "(\"Epilepsy\"[Mesh] OR \"Seizure Disorders\"[Mesh]) AND (\"Drug Resistance\"[Mesh] OR \"Anticonvulsant Therapy\"[Mesh]) AND (\"Treatment Outcome\"[Mesh] OR \"Efficacy\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Vagus Nerve Stimulation\"[Mesh] OR \"Ketogenic Diet\"[Mesh] OR \"Lamotrigine\"[Subheading] OR \"Levetiracetam\"[Subheading])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Surgical Procedures, Elective\"[Mesh] OR \"Epilepsy Surgery\"[Mesh] OR \"Resective Epilepsy Surgery\"[Mesh])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Pharmacological Therapy\"[Mesh] OR \"Antiepileptic Drugs\"[Mesh] OR \"Adjunctive Therapy\"[Mesh])", + "(\"Epilepsy\"[Mesh] AND \"Drug Resistance\"[Mesh]) AND (\"Neurostimulation, Transcranial, Magnetic\"[Mesh] OR \"Transcranial Direct Current Stimulation\"[Mesh] OR \"Transcranial Alternating Current Stimulation\"[Mesh])" + ], + "papers": { + "28555455": { + "title": "[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term follow-up]", + "abstract": "5. Rev Neurol. 2017 Jun 1;64(11):496-501.\n\n[Vagus nerve stimulation: treatment of 158 pediatric patients with a long-term \nfollow-up].\n\n[Article in Spanish; Abstract available in Spanish from the publisher]\n\nFlesler S(1), Reyes G(1), Fortini S(1), Ramos B(1), Cersosimo R(1), Bartuluchi \nM(1), Caraballo R(1).\n\nAuthor information:\n(1)Hospital Nacional de Pediatria J. P. Garrahan, 1818 Buenos Aires, Argentina.\n\nAIM: To describe a series of patients with drug resistant epilepsy treated with \nvagus nerve stimulation in a national pediatric hospital, evaluating efficacy, \nsafety and tolerability.\nPATIENTS AND METHODS: A retrospective analysis of 158 pediatric patients with \nepilepsy resistant to pharmacological and non pharmacological treatment \nincluding surgery that were treated with vagus nerve stimulation between \n2001-2015. Patients with progressive encephalopathies, and congenital heart \ndisease were excluded.\nRESULTS: 158 patients (80 male) were included, with a mean age at implantation \nof 11.4 years and a mean age at evolution of epilepsy of 9.5 years. Time of \nfollow-up: 1-15 years (median: 6.9 years). Patient's age at this time: 2-31 \nyears (median: 14.1 years). Effectiveness: 66.5% of patients showed more or \nequal at 50% of seizure control at 24 months of implant. Just three patients \nshowed severe side effects (1.8%). Minor side effects were seen in 26 patients \n(16.4%). Without side effects: 129 (81.8%).\nCONCLUSION: Vagus nerve stimulation is an effective, tolerable and safe therapy \nin our pediatric series with refractory epilepsy.\n\nPublisher: TITLE: Estimulador del nervio vago: tratamiento en 158 pacientes \npediatricos con un largo seguimiento.\nObjetivo. Describir una poblacion pediatrica de pacientes con epilepsia \nfarmacorresistente tratada con estimulador del nervio vago en un hospital \nnacional de pediatria, evaluando la eficacia, la tolerabilidad y la seguridad \ndel tratamiento. Pacientes y metodos. Se realizo un analisis retrospectivo de \n158 pacientes pediatricos seguidos por epilepsia refractaria al tratamiento \nfarmacologico y no farmacologico, incluida la cirugia, que fueron tratados con \nestimulador del nervio vago entre los a\u00f1os 2001 y 2015. Se excluyeron pacientes \ncon encefalopatias evolutivas y cardiopatias congenitas. Resultados. Se \nincluyeron 158 pacientes (80 varones) con una edad media de implante de 11,4 \na\u00f1os y un tiempo de evolucion de epilepsia preimplante de 9,5 a\u00f1os. El tiempo de \nseguimiento fue de 1-15 a\u00f1os (mediana: 6,9 a\u00f1os); la edad actual de los \npacientes, 2-31 a\u00f1os (mediana: 14,1 a\u00f1os). A los 24 meses postimplante, un 66,5% \nde los pacientes presento una mejoria mayor o igual al 50% de las crisis \nprevias. Solo tres pacientes (1,8%) presentaron efectos adversos graves, 26 \n(16,4%) mostraron efectos adversos menores y 129 (81,8%) no mostraron efectos \nadversos al tratamiento. Conclusion. La terapia con estimulador del nervio vago \nen esta serie pediatrica con epilepsia refractaria fue eficaz, bien tolerada y \nsegura.\n\nPMID: 28555455 [Indexed for MEDLINE]", + "authors": "[Article in Spanish; Abstract available in Spanish from the publisher]", + "journal": "Rev Neurol", + "year": "2017" + }, + "30143957": { + "title": "Expected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve Stimulation Therapy for Drug-Resistant Epilepsy", + "abstract": "4. Adv Ther. 2018 Oct;35(10):1686-1696. doi: 10.1007/s12325-018-0775-0. Epub 2018\n Aug 24.\n\nExpected Budget Impact and Health Outcomes of Expanded Use of Vagus Nerve \nStimulation Therapy for Drug-Resistant Epilepsy.\n\nPurser MF(1), Mladsi DM(2), Beckman A(3), Barion F(4), Forsey J(4).\n\nAuthor information:\n(1)RTI Health Solutions, Research Triangle Park, NC, USA. mpurser@rti.org.\n(2)RTI Health Solutions, Research Triangle Park, NC, USA.\n(3)LivaNova USA, Inc., Houston, TX, USA.\n(4)LivaNova PLC, London, UK.\n\nErratum in\n Adv Ther. 2018 Oct;35(10):1697. doi: 10.1007/s12325-018-0787-9.\n\nINTRODUCTION: The objective was to estimate, from the perspective of a managed \ncare organization in the United States, the budget impact and effect on health \noutcomes of expanded use of vagus nerve stimulation [VNS (VNS Therapy\u00ae)] among \npatients aged\u2009\u2265\u200912\u00a0years with drug-resistant epilepsy (DRE) with partial-onset \nseizures.\nMETHODS: An Excel model was developed to compare the costs of continued \nanti-epileptic drug (AED) treatment with the costs of VNS plus AED treatment. \nThe number of people eligible for VNS was estimated using published prevalence \ndata and an estimate of the percentage of eligible patients currently without \nVNS. Costs included VNS device, placement, programming, and battery changes; \nadverse events associated with VNS (cough, voice alteration, device removal \nresulting from surgical site infection); AEDs; and seizure-related costs \naffected by seizure frequency, which affects resource utilization (i.e., \nhospitalizations, emergency department visits, neurologist visits). To estimate \nthe potential savings with VNS due to a reduction in seizure frequency, the \nbudget impact model uses the results of an underlying Markov model to estimate \nseizure-related costs by seizure frequency. Transitions occurred among four \nhealth states, defined by number of seizures per month (i.e., \nseizure-free,\u2009\u2264\u20091,\u2009>\u20091 to\u2009<\u200910,\u2009\u2265\u200910) on a 3-month cycle based on published \nclinical trials and registry data.\nRESULTS: VNS resulted in an estimated net cost savings, on average, over \n5\u00a0years, due to the expected reduction in seizure frequency. The initial cost of \nthe VNS device, placement, and programming was estimated to be offset 1.7\u00a0years \nafter VNS device placement. Reductions in hospitalizations were the main \ncontributor to the cost savings with VNS.\nCONCLUSIONS: VNS is a proven intervention that offers a long-term solution for \npatients with DRE by reducing seizure frequency, which leads to lower resource \nutilization and lower costs.\nFUNDING: LivaNova PLC.\n\nDOI: 10.1007/s12325-018-0775-0\nPMCID: PMC6182643\nPMID: 30143957 [Indexed for MEDLINE]\n\nConflict of interest statement: Alan Beckman is an employee of LivaNova PLC. \nFrancesca Barion is an employee of LivaNova PLC. John Forsey is an employee of \nLivaNova PLC. Molly Purser is an employee of RTI Health Solutions. Deirdre \nMladsi is an employee of RTI Health Solutions.", + "authors": "Purser MF, Mladsi DM, Beckman A et al.", + "journal": "Adv Ther", + "year": "2018" + }, + "31526890": { + "title": "Efficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy", + "abstract": "2. World Neurosurg. 2020 Jan;133:e448-e451. doi: 10.1016/j.wneu.2019.09.049. Epub\n 2019 Sep 14.\n\nEfficacy of Vagal Nerve Stimulation for Pharmacoresistant Poststroke Epilepsy.\n\nKubota Y(1), Nakamoto H(2), Miyao S(2), Kawamata T(3).\n\nAuthor information:\n(1)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan. Electronic address: kubota.yuichi@twmu.ac.jp.\n(2)Department of Neurosurgery, Stroke and Epilepsy Center, TMG Asaka Medical \nCenter, Saitama, Japan; Department of Neurosurgery, Tokyo Women's Medical \nUniversity, Tokyo, Japan.\n(3)Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.\n\nBACKGROUND: Vagal nerve stimulation (VNS) is an alternative palliative therapy \nfor pharmacoresistant epilepsy. It has been reported to be effective for both \nfocal and generalized epilepsy; however, most of the relevant studies have \ninvolved children or young patients. Some patients develop intractable epilepsy \nafter stroke, despite taking antiepileptic drugs (AEDs). In this study, we \ninvestigated the efficacy of VNS for pharmacoresistant poststroke epilepsy \n(PPSE).\nMETHODS: We retrospectively studied 10 patients who underwent vagal nerve \nstimulator implantation for poststroke epilepsy after the seizures had proved \nrefractory to appropriate AEDs. The seizure outcome was evaluated using the \nMcHugh classification 2 years after the implantation.\nRESULTS: In total, 4 patients (40%) remained seizure-free throughout the 2-year \nduration. In addition, seizures were reduced by >50% after 2 years in 6 patients \n(60%). McHugh classification was class I for 5 patients and class II for 5 \npatients. Neither intraoperative complications nor postoperative adverse effects \nwere reported. The average intensity of VNS was 1.75 mA.\nCONCLUSIONS: In this small study, VNS proved to be a safe and effective therapy \nfor PPSE. Patients with poststroke epilepsy experience physical or mental \ndecline; therefore, it is important to control seizures in them to avoid \ndeterioration in their quality of daily life.\n\nCopyright \u00a9 2019 Elsevier Inc. All rights reserved.\n\nDOI: 10.1016/j.wneu.2019.09.049\nPMID: 31526890 [Indexed for MEDLINE]", + "authors": "Kubota Y, Nakamoto H, Miyao S et al.", + "journal": "World Neurosurg", + "year": "2020" + }, + "32847092": { + "title": "Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy", + "abstract": "1. Int J Environ Res Public Health. 2020 Aug 24;17(17):6150. doi: \n10.3390/ijerph17176150.\n\nHealth Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant \nEpilepsy.\n\nMarras CE(1), Colicchio G(2), De Palma L(3), De Benedictis A(1), Di Gennaro \nG(4), Cavaliere M(1)(5), Cesaroni E(6), Consales A(7), Asioli S(8), Caulo M(9), \nVillani F(10), Zamponi N(6).\n\nAuthor information:\n(1)Neurosurgery Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 Children \nHospital, 00165 Rome, Italy.\n(2)Department of Neurosurgery, UCSC Gemelli University Hospital, 00167 Rome, \nItaly.\n(3)Pediatric Neurology Unit, Department of Neuroscience, IRCCS Bambino Ges\u00f9 \nChildren Hospital, 00165 Rome, Italy.\n(4)Neurology Unit, IRCCS Neuromed Institute, 86077 Pozzilli, Italy.\n(5)Institute of Neurosurgery, University of Milan Bicocca, 20900 Milan, Italy.\n(6)Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy.\n(7)Pediatric Neurosurgery Unit, G. Gaslini Hospital, 16147 Genoa, Italy.\n(8)Department of Biomedical and Neuromotor Sciences, Section of Anatomic \nPathology, Bellaria Hospital, University of Bologna, 40139 Bologna, Italy.\n(9)Department of Neuroscience, Imaging and Clinical Sciences, University of \nChieti, 66100 Chieti, Italy.\n(10)Division of Clinical Neurophysiology and Epilepsy Center, IRCCS, San Martino \nHospital, 16132 Genoa, Italy.\n\nBackground: Vagus nerve stimulation (VNS) is a palliative treatment for medical \nintractable epileptic syndromes not eligible for resective surgery. Health \ntechnology assessment (HTA) represents a modern approach to the analysis of \ntechnologies used for healthcare. The purpose of this study is to assess the \nclinical, organizational, financial, and economic impact of VNS therapy in \ndrug-resistant epilepsies and to establish the congruity between costs incurred \nand health service reimbursement. Methods: The present study used an HTA \napproach. It is based on an extensive detailed bibliographic search on databases \n(Medline, Pubmed, Embase and Cochrane, sites of scientific societies and \ninstitutional sites). The HTA study includes the following issues: (a) social \nimpact and costs of the disease; (b) VNS eligibility and clinical results; (c) \nquality of life (QoL) after VNS therapy; (d) economic impact and productivity \nregained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS \nas an effective treatment with a potential positive impact on social aspects and \non quality of life. The diagnosis-related group (DRG) financing, both on \nnational and regional levels, does not cover the cost of the medical device. \nThere was an evident insufficient coverage of the DRG compared to the full cost \nof implanting the device. Conclusions: VNS is a palliative treatment for \nreducing seizure frequency and intensity. Despite its economic cost, VNS should \nimprove patients' quality of life and reduce care needs.\n\nDOI: 10.3390/ijerph17176150\nPMCID: PMC7504285\nPMID: 32847092 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no conflict of interest.", + "authors": "Marras CE, Colicchio G, De Palma L et al.", + "journal": "Int J Environ Res Public Health", + "year": "2020" + }, + "35883201": { + "title": "Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?", + "abstract": "5. Brain. 2022 Nov 21;145(11):3755-3762. doi: 10.1093/brain/awac275.\n\nExpedited epilepsy surgery prior to drug resistance in children: a frontier \nworth crossing?\n\nHale AT(1), Chari A(2)(3), Scott RC(3)(4)(5), Helen Cross J(3)(5), Rozzelle \nCJ(1), Blount JP(1), Tisdall MM(2)(3).\n\nAuthor information:\n(1)Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, AL, \nUSA.\n(2)Department of Neurosurgery, Great Ormond Street Hospital, London, UK.\n(3)Developmental Neurosciences, Great Ormond Street Institute of Child Health, \nUniversity College London, London, UK.\n(4)Department of Paediatric Neurology, Nemours Children's Hospital, Wilmington, \nDE, USA.\n(5)Department of Paediatric Neurology, Great Ormond Street Hospital, London, UK.\n\nEpilepsy surgery is an established safe and effective treatment for selected \ncandidates with drug-resistant epilepsy. In this opinion piece, we outline the \nclinical and experimental evidence for selectively considering epilepsy surgery \nprior to drug resistance. Our rationale for expedited surgery is based on the \nobservations that (i) a high proportion of patients with lesional epilepsies \n(e.g. focal cortical dysplasia, epilepsy-associated tumours) will progress to \ndrug resistance; (ii) surgical treatment of these lesions, especially in \nnon-eloquent areas of brain, is safe; and (iii) earlier surgery may be \nassociated with better seizure outcomes. Potential benefits beyond seizure \nreduction or elimination include less exposure to antiseizure medications, which \nmay lead to improved developmental trajectories in children and optimize \nlong-term neurocognitive outcomes and quality of life. Further, there exists \nemerging experimental evidence that brain network dysfunction exists at the \nonset of epilepsy, where continuing dysfunctional activity could exacerbate \nnetwork perturbations. This in turn could lead to expanded seizure foci and \ncontribution to the comorbidities associated with epilepsy. Taken together, we \nrationalize that epilepsy surgery, in carefully selected cases, may be \nconsidered prior to drug resistance. Last, we outline the path forward, \nincluding the challenges associated with developing the evidence base and \nimplementing this paradigm into clinical care.\n\n\u00a9 The Author(s) 2022. Published by Oxford University Press on behalf of the \nGuarantors of Brain. All rights reserved. For permissions, please e-mail: \njournals.permissions@oup.com.\n\nDOI: 10.1093/brain/awac275\nPMID: 35883201 [Indexed for MEDLINE]", + "authors": "Hale AT, Chari A, Scott RC et al.", + "journal": "Brain", + "year": "2022" + }, + "37352888": { + "title": "Drug resistance in epilepsy", + "abstract": "3. Lancet Neurol. 2023 Aug;22(8):723-734. doi: 10.1016/S1474-4422(23)00151-5.\nEpub 2023 Jun 20.\n\nDrug resistance in epilepsy.\n\nPerucca E(1), Perucca P(2), White HS(3), Wirrell EC(4).\n\nAuthor information:\n(1)Department of Medicine, Austin Health, University of Melbourne, Melbourne, \nVIC, Australia; Department of Neuroscience, Central Clinical School, Monash \nUniversity, Melbourne, VIC, Australia. Electronic address: \nemilio.perucca@unimelb.edu.au.\n(2)Department of Medicine, Austin Health, University of Melbourne, Melbourne, \nVIC, Australia; Department of Neuroscience, Central Clinical School, Monash \nUniversity, Melbourne, VIC, Australia; Bladin-Berkovic Comprehensive Epilepsy \nProgram, Department of Neurology, Austin Health, Melbourne, VIC, Australia; \nDepartment of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia; \nDepartment of Neurology, Alfred Health, Melbourne, VIC, Australia.\n(3)Department of Pharmacy, School of Pharmacy, University of Washington, \nSeattle, WA, USA.\n(4)Divisions of Child and Adolescent Neurology and Epilepsy, Department of \nNeurology, Mayo Clinic, Rochester, MN, USA.\n\nDrug resistance is estimated to affect about a third of individuals with \nepilepsy, but its prevalence differs in relation to the epilepsy syndrome, the \ncause of epilepsy, and other factors such as age of seizure onset and presence \nof associated neurological deficits. Although drug-resistant epilepsy is not \nsynonymous with unresponsiveness to any drug treatment, the probability of \nachieving seizure freedom on a newly tried medication decreases with increasing \nnumber of previously failed treatments. After two appropriately used antiseizure \nmedications have failed to control seizures, individuals should be referred \nwhenever possible to a comprehensive epilepsy centre for diagnostic \nre-evaluation and targeted management. The feasibility of epilepsy surgery and \nother treatments, including those targeting the cause of epilepsy, should be \nconsidered early after diagnosis. Substantial evidence indicates that a delay in \nidentifying an effective treatment can adversely affect ultimate outcome and \ncarry an increased risk of cognitive disability, other comorbidities, and \npremature mortality. Research on mechanisms of drug resistance and novel \ntherapeutics is progressing rapidly, and potentially improved treatments, \nincluding those targeting disease modification, are on the horizon.\n\nCopyright \u00a9 2023 Elsevier Ltd. All rights reserved.\n\nDOI: 10.1016/S1474-4422(23)00151-5\nPMID: 37352888 [Indexed for MEDLINE]\n\nConflict of interest statement: Declaration of interests EP received speaker \nfees or fees from consulting or participation in Advisory Boards or Data Safety \nMonitoring Board from Angelini, Arvelle, Biopas, Eisai, GW Pharma, Janssen, PMI \nLife Sciences, Sanofi group of companies, Shackelford Pharma, SKL Life Science, \nSun Pharma, Takeda, UCB Pharma, Xenon Pharma, and Zogenix, and royalties from \nWiley, Elsevier, and Wolters Kluwers, all outside the submitted work. He was \nimmediate Past-President of the ILAE for the 2017\u201321 term and an Associate \nEditor of Epileptic Disorders from 2020 to 2022. PP has received speaker \nhonoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, \nNovartis, Sun Pharma, Supernus, the Limbic, and UCB Pharma, outside the \nsubmitted work. He is an Associate Editor for Epilepsia Open. HSW has received \ngrant funding from UCB Pharma, Eisai Pharmaceuticals, and Neurelis, and \nconsultant fees from GW Pharmaceuticals, Neurelis, Takeda Pharmaceuticals, SK \nLife Sciences, and JAZZ Pharmaceuticals, and speaker honoraria from SK \nPharmaceuticals, Takeda Pharmaceuticals, and UCB Pharma. ECW has served as a \npaid consultant for Encoded Therapeutics, Amicus, Acadia, Neurocrine, and \nBioMarin. She is the Editor-in-Chief of Epilepsy.com.", + "authors": "Perucca E, Perucca P, White HS et al.", + "journal": "Lancet Neurol", + "year": "2023" + }, + "39285222": { + "title": "Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance", + "abstract": "2. Sci Rep. 2024 Sep 16;14(1):21606. doi: 10.1038/s41598-024-72683-7.\n\nGenotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment \nefficacy and drug resistance.\n\nNguyen YTM(#)(1)(2), Vu BQ(#)(3)(4), Nguyen DK(5), Quach NV(5), Bui LT(3), Hong \nJ(6)(7), Bui CB(8)(9).\n\nAuthor information:\n(1)Department of Biotechnology, International University, Vietnam National \nUniversity Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(2)Unit of AI Genomics, DNA Medical Technology, Ho Chi Minh City, Vietnam.\n(3)Institute of Food and Biotechnology, Can Tho University, Can Tho City, \nVietnam.\n(4)Faculty of Computer Science, University of Information Technology, Vietnam \nNational University Ho Chi Minh City, Ho Chi Minh City, Vietnam.\n(5)Department of Neurology, City Children's Hospital, Ho Chi Minh City, Vietnam.\n(6)Department of Medical Device Management and Research, Samsung Advanced \nInstitute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, \nSamsung Medical Center, Seoul, South Korea.\n(7)HnB Genomics, Ulsan, South Korea.\n(8)University of Health Sciences, Vietnam National University Ho Chi Minh City, \nHo Chi Minh, Vietnam. bcbao@medvnu.edu.vn.\n(9)Unit of Molecular Biology, City Children's Hospital, Ho Chi Minh City, \nVietnam. bcbao@medvnu.edu.vn.\n(#)Contributed equally\n\nNeonatal intensive care unit (NICU), particularly in treating developmental and \nepileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep \nunderstanding of their complex etiologies and treatment responses. After \nexcluding treatable cases such as infectious or autoimmune encephalitis, our \nfocus shifted to a more challenging subgroup of 59 patients for in-depth genetic \nanalysis using exome sequencing (ES). The ES analysis identified 40 genetic \nabnormalities, significantly including de novo variants. Notably, we found \nstructural variation as duplications in regions 2q24.3, including SCN1A and \nSCN2A were observed in 7 cases. These genetic variants, impacting ion channels, \nglucose transport, transcription regulation, and kinases, play a crucial role in \ndetermining medication efficacy. More than one-third (34.2%) of patients with \nDEE had an unfavorable response to anti-seizure medications (ASMs) in the \nchronic phase. However, since the ketogenic supplementary diet showed a positive \neffect, more than three-quarters (80%) of these drug-resistant patients improved \nduring a 3-month follow-up. In contrast, the ME had a lower adverse reaction \nrate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and \n10 cases with unidentified genetic etiologies. This study suggests the potential \nof categorizing drug-resistant variants and that a ketogenic diet could be \nbeneficial in managing DEE and ME. It also opens new perspectives on the \nmechanisms of the ketogenic diet on the discovered genetic variants.\n\n\u00a9 2024. The Author(s).\n\nDOI: 10.1038/s41598-024-72683-7\nPMCID: PMC11405402\nPMID: 39285222 [Indexed for MEDLINE]\n\nConflict of interest statement: The authors declare no competing interests.", + "authors": "Nguyen YTM(#), Vu BQ(#), Nguyen DK et al.", + "journal": "Sci Rep", + "year": "2024" + }, + "39954158": { + "title": "ABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and toxicity in Algerian patients with epilepsy: initial findings report", + "abstract": "1. Neurogenetics. 2025 Feb 15;26(1):29. doi: 10.1007/s10048-025-00807-w.\n\nABCB1 c.3435 C\u2009>\u2009T (rs1045642) as a biomarker for carbamazepine efficacy and \ntoxicity in Algerian patients with epilepsy: initial findings report.\n\nRiffi R(1), Boughrara W(2)(3)(4), Aberkane MS(2)(5), Ilias W(2)(6), Bouchetara \nMS(7)(8), Berrebbah AA(4), Belhoucine F(4), Chentouf A(7)(9)(8).\n\nAuthor information:\n(1)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria. riffi.rachda@essb-oran.edu.dz.\n(2)\u00c9cole Sup\u00e9rieure en Sciences Biologiques d'Oran (ESSBO), BP 1042, Saim \nMohamed 31003, Oran, Algeria.\n(3)Service de Cytog\u00e9n\u00e9tique Et de Biologie Mol\u00e9culaire de L'\u00e9tablissement \nHospitalo-Universitaire d'Oran, Oran, Algeria.\n(4)Laboratoire de Toxicologie, Environnement et sant\u00e9, LATES, USTO-MB, Oran, \nUniversit\u00e9 des Sciences et Technologie Oran-Mohamed Boudiaf USTO-MB, El Mnaouar, \nBP 1505, Bir El Djir 31000, Oran, Algeria.\n(5)D\u00e9partement de Pharmacie, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran 1, Oran, \nAlgeria.\n(6)Laboratoire de G\u00e9n\u00e9tique Mol\u00e9culaire Et Cellulaire (LGMC), Universit\u00e9 Des \nSciences Et de La Technologie d'Oran Mohamed Boudiaf (USTO-MB), BP 1505, El \nMnaouar, Bir El Djir 31000, Oran, Algeria.\n(7)Service de Neurologie, \u00c9tablissement Hospitalier Universitaire d'Oran, Oran, \nAlgeria.\n(8)Universit\u00e9 Oran1 Ahmed Ben Bella, Oran, Algeria.\n(9)Laboratoire de Recherche ACCIPED, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Oran1, \nOran, Algeria.\n\nEpilepsy is among the most prevalent serious neurological disorders, affecting \nover 70 million people worldwide, in Algeria, the prevalence of epilepsy was \nestimated to be eight times more common. Carbamazepine is frequently the \nfirst-line treatment, making early prediction of patient response essential for \npersonalized care. This approach helps reduce adverse effects and healthcare \ncosts, while enhancing patient outcomes. This study aims to explore the link \nbetween the ABCB1 c.3435C\u2009>\u2009T genetic variation and Carbamazepine resistance and \ntoxicity in Algerian patients with epilepsy, with a focus on the impact of \ngenetic variations on Carbamazepine plasma concentrations and treatment \noutcomes. Ninety-eight Algerian patients with epilepsy were recruited and \ncategorized as either drug-responsive or drug-resistant based on their clinical \nresponse to CBZ treatment. Genotyping of the ABCB1 c.3435 C\u2009>\u2009T polymorphism was \nperformed using Polymerase Chain Reaction-Restriction Fragment Length \nPolymorphism (PCR-RFLP) method, and CBZ plasma levels were measured to assess \nits effect on metabolism. Clinical data, including drug response, therapy type, \nand adverse drug reactions (ADRs), were collected and analyzed. For the \nstatistical analysis we used chi-squared tests and Exact Fisher's for \ncorrections. Our findings show no significant association between the ABCB1 \nc.3435C\u2009>\u2009T genotypes with carbamazepine resistance (p\u2009=\u20090,1) nor incidence of \nadverse reactions. This polymorphism also indicated no statistically significant \nlink with Carbamazepine plasma levels. The sample size in this study might be \nlimitation; therefore, expanded investigations on Algerian population are \nneeded. Although this study indicates no significant correlation of the ABCB1 \nc.3435C\u2009>\u2009T polymorphism with influencing CBZ Pharmacoresistance and therapeutic \noutcomes, larger-scale-studies are required to confirm these results and assess \ntheir reliability.\n\n\u00a9 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, \npart of Springer Nature.\n\nDOI: 10.1007/s10048-025-00807-w\nPMID: 39954158 [Indexed for MEDLINE]\n\nConflict of interest statement: Declarations. Ethics approval: The ethical board \nof Neurology Department of the University Hospital of Oran, Algeria approved \nthis study. Consent to participate: In accordance with the Declaration of \nHelsinki, all participants were fully informed about the objectives of the \nstudy, and written informed consent was obtained prior to their inclusion. \nIndividuals who chose not to provide consent were excluded from participation. \nConsent for publication: Not applicable. Competing interests: The authors \ndeclare no competing interests. Clinical trial number: Not applicable. Clinical \ntrial: Not applicable.", + "authors": "Riffi R, Boughrara W, Aberkane MS et al.", + "journal": "Neurogenetics", + "year": "2025" + } + } + }, { "id": "20260503123342", "timestamp": "May 03, 12:33",