Background: Drug-resistant epilepsy can be defined as the existence of seizures within 6 months, despite adequate therapy regimens with one or more antiepileptic drugs. Epilepsy surgery has been the standard therapy to help those patients who suffer from drug-resistant epilepsy. The goal of this surgery is to halt or reduce the intensity of seizures. This literature review aims to provide an overview of existing surgical procedures for the treatment of drug-resistant epilepsy and the degree of seizure control they provide based on available literature. Methods: Data were collected from medical journal databases, aggregators, and individual publications. The most used databases were PubMed, Medline and NCBI. Some of the keywords used to search these databases include: “drug resistant epilepsy”, “seizure control”, and “neuro surgery”. Results: Epileptic surgery is divided into resective and non-resective procedures. Studies have shown that a full resection of the epileptogenic brain area increases the probability of seizure eradication, however, the risks of postoperative impairments grow as the resection area is extended. On the other hand, patients who are unsuitable for seizure focus removal by resective surgery, such as those with multifocal seizures or overlapping epileptogenic zone with a functional cortex, may benefit from non-resective sur gical options such as Vagus Nerve Stimulation and Responsive Neurostimulation. Conclusion: This literature review discusses the comprehensive treatment of epilepsy, especially the surgical treatment of drug-resistant epilepsy. The reviewed studies have shown that epilepsy surgery has promising outcomes in achieving seizure freedom/reducing seizure frequency with minimal adverse effects when performed correctly with the appropriate choice of surgical candidates.
World Health Organization (2023) Epilepsy. https://www.who.int/news-room/fact-sheets/detail/epilepsy
Avakyan, G.N., Blinov, D.V., Lebedeva, A.V., Burd, S.G. and Avakyan, G.G. (2017) Ilae Classification of the Epilepsies: The 2017 Revision and Update. Epilepsy and Paroxysmal Conditions, 9, 6-25. https://doi.org/10.17749/2077-8333.2017.9.1.006-025
Magiorkinis, E., Diamantis, A., Sidiropoulou, K. and Panteliadis, C. (2014) Highights in the History of Epilepsy: The Last 200 Years. Epilepsy Research and Treatment, 2014, Article ID: 582039. https://doi.org/10.1155/2014/582039
Passos, G. (2020) History and Evolution of Epilepsy Surgery [História e evolução da cirurgia para epilepsia]. Neurosurgery, 39, 27-32. https://doi.org/10.1055/s-0037-1604029
Kaculini, C.M., Tate-Looney, A.J. and Seifi, A. (2021) The History of Epilepsy: From Ancient Mystery to Modern Misconception. Cureus, 13, e13953. https://doi.org/10.7759/cureus.13953
Feindel, W., Leblanc, R. and De Almeida, A.N. (2009) Epilepsy Surgery: Historical Highlights 1909-2009. Epilepsia, 50, 131-151. https://doi.org/10.1111/j.1528-1167.2009.02043.x
Meador, K.J., Loring, D.W. and Flanigin, H.F. (1989) History of Epilepsy Surgery. Journal of Epilepsy, 2, 21-25. https://doi.org/10.1016/0896-6974(89)90054-6
Strauss, K.I. and Elisevich, K.V. (2016) Brain Region and Epilepsy-Associated Differences in Inflammatory Mediator Levels in Medically Refractory Mesial Temporal Lobe Epilepsy. Journal of Neuroinflammation, 13, Article No. 270. https://doi.org/10.1186/s12974-016-0727-z
Alawieh, A., Langley, E.F., Weber, S., Adkins, D. and Tomlinson, S. (2018) Identifying the Role of Complement in Triggering Neuroinflammation after Traumatic Brain Injury. Journal of Neuroscience, 38, 2519-2532. https://doi.org/10.1523/JNEUROSCI.2197-17.2018
Sun, J., Jiang, T., Gu, F., Ma, D. and Liang, J. (2020) TMT-Based Proteomic Analysis of Plasma from Children with Rolandic Epilepsy. Disease Markers, 2020, Article ID: 8840482. https://doi.org/10.1155/2020/8840482
Choi, J. and Koh, S. (2008) Role of Brain Inflammation in Epileptogenesis. Yonsei Medical Journal, 49, 1-18. https://doi.org/10.3349/ymj.2008.49.1.1
Uludag, I.F., Bilgin, S., Zorlu, Y., Tuna, G. and Kirkali, G. (2013) Interleukin-6, Interleukin-1 β and Interleukin-1 Receptor Antagonist Levels in Epileptic Seizures. Seizure, 22, 457-461. https://doi.org/10.1016/j.seizure.2013.03.004
Lazarowski, A., Czornyj, L., Lubienieki, F., Girardi, E., Vazquez, S. and D’Giano, C. (2007) ABC Transporters during Epilepsy and Mechanisms Underlying Multidrug Resistance in Refractory Epilepsy. Epilepsia, 48, 140-149. https://doi.org/10.1111/j.1528-1167.2007.01302.x
Sisodiya, S.M., Lin, W.R., Harding, B.N., Squier, M.V. and Thom, M. (2002) Drug Resistance in Epilepsy: Expression of Drug Resistance Proteins in Common Causes of Refractory Epilepsy. Brain, 125, 22-31. https://doi.org/10.1093/brain/awf002
Tang, F., Hartz, A.M.S. and Bauer, B. (2017) Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers. Frontiers in Neurology, 8, Article 301. https://doi.org/10.3389/fneur.2017.00301
Rogawski, M.A. and Johnson, M.R. (2008) Intrinsic Severity as a Determinant of Antiepileptic Drug Refractoriness. Epilepsy Currents, 8, 127-130. https://doi.org/10.1111/j.1535-7511.2008.00272.x
Depondt, C. (2006) The Potential of Pharmacogenetics in the Treatment of Epilepsy. European Journal of Pediatric Neurology, 10, 57-65. https://doi.org/10.1016/j.ejpn.2005.11.009
Kobow, K. and Blümcke, I. (2018) Epigenetics in Epilepsy. Neuroscience Letters, 667, 40-46. https://doi.org/10.1016/j.neulet.2017.01.012
Remy, S., Gabriel, S., Urban, B.W., Dietrich, D., Lehmann, T.N., Elger, C.E., et al. (2003) A Novel Mechanism Underlying Drug Resistance in Chronic Epilepsy. Annals of Neurology, 53, 469-479. https://doi.org/10.1002/ana.10473
Bazhanova, E.D., Kozlov, A.A. and Litovchenko, A.V. (2021) Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review. Brain Sciences, 11, Article 663. https://doi.org/10.3390/brainsci11050663
Lüders, H.O. (2008) Textbook of Epilepsy Surgery. Informa Healthcare, London.
Kovac, S., Vakharia, V.N., Scott, C. and Diehl, B. (2017) Invasive Epilepsy Surgery Evaluation. Seizure, 44, 125-136. https://doi.org/10.1016/j.seizure.2016.10.016
Engel, J., Babb, T.L. and Crandall, P.H. (1989) Surgical Treatment of Epilepsy: Opportunities for Research into Basic Mechanisms of Human Brain Function. In: Broggi, G., Burzaco, J., Hitchcock, E.R., Meyerson, B.A. and Tóth, S., Eds., Advances in Stereotactic and Functional Neurosurgery 8, Springer, Vienna, 3-8. https://doi.org/10.1007/978-3-7091-9029-6_1
Panayiotopoulos, C.P. (2011) The New ILAE Report on Terminology and Concepts for Organization of Epileptic Seizures: A Clinician’s Critical View and Contribution. Epilepsia, 52, 2155-2160. https://doi.org/10.1111/j.1528-1167.2011.03288.x
MGH Epilepsy Service (2023) Epilepsy Surgery Outcome Scales. https://seizure.mgh.harvard.edu/engel-surgical-outcome-scale/
Yap, J.Y.Y., Keatch, C., Lambert, E., Woods, W., Stoddart, P.R. and Kameneva, T. (2020) Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Frontiers in Neuroscience, 14, Article 284. https://doi.org/10.3389/fnins.2020.00284
Chang, E.F., Englot, D.J. and Vadera, S. (2015) Minimally Invasive Surgical Approaches for Temporal Lobe Epilepsy. Epilepsy and Behavior, 47, 24-33. https://doi.org/10.1016/j.yebeh.2015.04.033
Sherman, E.M.S., Wiebe, S., Fay-Mcclymont, T.B., Tellez-Zenteno, J., Metcalfe, A., Hernandez-Ronquillo, L., et al. (2011) Neuropsychological Outcomes after Epilepsy Surgery: Systematic Review and Pooled Estimates. Epilepsia, 52, 857-869. https://doi.org/10.1111/j.1528-1167.2011.03022.x
Spencer, D.D., Spencer, S.S., Mattson, R.H., Williamson, P.D. and Novelly, R.A. (1984) Access to the Posterior Medial Temporal Lobe Structures in the Surgical Treatment of Temporal Lobe Epilepsy. Neurosurgery, 15, 667-671. https://doi.org/10.1227/00006123-198411000-00005
Engel, J., McDermott, M.P., Wiebe, S., Langfitt, J.T., Stern, J.M., Dewar, S., et al. (2012) Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy: A Randomized Trial. JAMA, 307, 922-930. https://doi.org/10.1001/jama.2012.220
Chacón, L.M.M., González González, J., Ríos Castillo, M., Berrillo Batista, S., García-Ramo, K.B., Santos Santos, A., et al. (2021) Surgical Outcome in Extratemporal Epilepsies Based on Multimodal Pre-Surgical Evaluation and Sequential Intraoperative Electrocorticography. Behavioral Sciences, 11, Article 30. https://doi.org/10.3390/bs11030030
Von Lehe, M., Wellmer, J., Urbach, H., Schramm, J., Elger, C.E. and Clusmann, H. (2009) Insular Lesionectomy for Refractory Epilepsy: Management and Outcome. Brain, 132, 1048-1056. https://doi.org/10.1093/brain/awp047
Jehi, L.E, O’Dwyer, R., Najm, I., Alexopoulos, A. and Bingaman, W. (2009) A Longitudinal Study of Surgical Outcome and Its Determinants following Posterior Cortex Epilepsy Surgery. Epilepsia, 50, 2040-2052. https://doi.org/10.1111/j.1528-1167.2009.02070.x
Kazemi, N.J., So, E.L., Mosewich, R.K., O’Brien, T.J., Cascino, G.D., Trenerry, M.R., et al. (1997) Resection of Frontal Encephalomalacias for Intractable Epilepsy: Outcome and Prognostic Factors. Epilepsia, 38, 670-677. https://doi.org/10.1111/j.1528-1157.1997.tb01236.x
Jeha, L.E., Najm, I., Bingaman, W., Dinner, D., Widdess-Walsh, P. and Lüders, H. (2007) Surgical Outcome and Prognostic Factors of Frontal Lobe Epilepsy Surgery. Brain, 130, 574-584. https://doi.org/10.1093/brain/awl364
Heo, W., Kim, J.S., Chung, C.K. and Lee, S.K. (2018) Relationship between Cortical Resection and Visual Function after Occipital Lobe Epilepsy Surgery. Journal of Neurosurgery, 129, 524-532. https://doi.org/10.3171/2017.5.JNS162963
Johns Hopkins Medicine (2023) Laser Interstitial Thermal Therapy. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/laser-interstitial-thermal-therapy
Medvid, R., Ruiz, A., Komotar, R.J., Jagid, J.R., Ivan, M.E., Quencer, R.M., et al. (2015) Current Applications of MRI-Guided Laser Interstitial Thermal Therapy in the Treatment of Brain Neoplasms and Epilepsy: A Radiologic and Neurosurgical Overview. American Journal of Neuroradiology, 36, 1998-2006. https://doi.org/10.3174/ajnr.A4362
Waseem, H., Osborn, K.E., Schoenberg, M.R., Kelley, V., Bozorg, A., Cabello, D., et al. (2015) Laser Ablation Therapy: An Alternative Treatment for Medically Resistant Mesial Temporal Lobe Epilepsy after Age 50. Epilepsy & Behavior, 51, 152-157. https://doi.org/10.1016/j.yebeh.2015.07.022
Calisto, A., Dorfmüller, G., Fohlen, M., Bulteau, C., Conti, A. and Delalande, O. (2014) Endoscopic Disconnection of Hypothalamic Hamartomas: Safety and Feasibility of Robot-Assisted, Thulium Laser-Based Procedures. Journal of Neurosurgery: Pediatrics, 14, 563-572. https://doi.org/10.3171/2014.8.PEDS13586
Clarke, D.F., Tindall, K., Lee, M. and Patel, B. (2014) Bilateral Occipital Dysplasia, Seizure Identification, and Ablation: A Novel Surgical Technique. Epileptic Disorders, 16, 238-243. https://doi.org/10.1684/epd.2014.0658
Singh, H., Essayed, W.I., Deb, S., Hoffman, C. and Schwartz, T.H. (2017) Minimally Invasive Robotic Laser Corpus Callosotomy: A Proof of Concept. Cureus, 9, e1021. https://doi.org/10.7759/cureus.1021
Shimamoto, S., Wu, C. and Sperling, M.R. (2019) Laser Interstitial Thermal Therapy in Drug-Resistant Epilepsy. Current Opinion in Neurology, 32, 237-245. https://doi.org/10.1097/WCO.0000000000000662
Hoppe, C., Witt, J.A., Helmstaedter, C., Gasser, T., Vatter, H. and Elger, C.E. (2017) Laser Interstitial Thermotherapy (LiTT) in Epilepsy Surgery. Seizure, 48, 45-52. https://doi.org/10.1016/j.seizure.2017.04.002
Landazuri, P., Shih, J., Leuthardt, E., Ben-Haim, S., Neimat, J., Tovar-Spinoza, Z., et al. (2020) A Prospective Multicenter Study of Laser Ablation for Drug Resistant Epilepsy—One Year Outcomes. Epilepsy Research, 167, Article ID: 106473. https://doi.org/10.1016/j.eplepsyres.2020.106473
Romanelli, P. and Anschel, D.J. (2006) Radiosurgery for Epilepsy. The Lancet Neurology, 5, 613-620. https://doi.org/10.1016/S1474-4422(06)70496-3
Nguyen, D.K. and Spencer, S.S. (2003) Recent Advances in the Treatment of Epilepsy. Archives of neurology, 60, 929-935. https://doi.org/10.1001/archneur.60.7.929
Dillon, W.P. and Barbaro, N. (1999) Noninvasive Surgery for Epilepsy: The Era of Image Guidance. American Journal of Neuroradiology, 20, 185-186.
Regis, J., Peragut, J.C., Rey, M., Samson, Y., Levriei, O., Porcheron, D., et al. (1995) First Selective Amygdalohippocampal Radiosurgery for ‘Mesial Temporal Lobe Epilepsy.’ Stereotactic and Functional Neurosurgery, 64, 193-201. https://doi.org/10.1159/000098779
Rheims, S., Fischer, C., Ryvlin, P., Isnard, J., Guenot, M., Tamura, M., et al. (2008) Long-Term Outcome of γ-Knife Surgery in Temporal Lobe Epilepsy. Epilepsy Research, 80, 23-29. https://doi.org/10.1016/j.eplepsyres.2008.03.003
Barbaro, N.M., Quigg, M., Broshek, D.K., Ward, M.M., Lamborn, K.R., Laxer, K.D., et al. (2009) A Multicenter, Prospective Pilot Study of γ Knife Radiosurgery for Mesial Temporal Lobe Epilepsy: Seizure Response, Adverse Events, and Verbal Memory. Annals of Neurology, 65, 167-175. https://doi.org/10.1002/ana.21558
Régis, J., Rey, M., Bartolomei, F., Vladyka, V., Liscak, R., Schröttner, O., et al. (2004) γ Knife Surgery in Mesial Temporal Lobe Epilepsy: A Prospective Multicenter Study. Epilepsia, 45, 504-515. https://doi.org/10.1111/j.0013-9580.2004.07903.x
Feng, E.S., Sui, C.B., Wang, T.X. and Sun, G.L. (2016) Stereotactic Radiosurgery for the Treatment of Mesial Temporal Lobe Epilepsy. Acta Neurologica Scandinavica, 134, 442-451. https://doi.org/10.1111/ane.12562
Hamdi, H., Albader, F., Spatola, G., Laguitton, V., Trebuchon, A., Bartolomei, F., et al. (2021) Long-Term Cognitive Outcome after Radiosurgery in Epileptic Hypothalamic Hamartomas and Review of the Literature. Epilepsia, 62, 1369-1381. https://doi.org/10.1111/epi.16896
Bottomley, J.M., LeReun, C., Diamantopoulos, A., Mitchell, S. and Gaynes, B.N. (2019) Vagus Nerve Stimulation (VNS) Therapy in Patients with Treatment Resistant Depression: A Systematic Review and Meta-Analysis. Comprehensive Psychiatry, 98, Article ID: 152156. https://doi.org/10.1016/j.comppsych.2019.152156
Mullan, S., Vailati, G., Karasick, J. and Mailis, M. (1967) Thalamic Lesions for the Control of Epilepsy. A Study of Nine Cases. Archives of Neurology, 16, 277-285. https://doi.org/10.1001/archneur.1967.00470210053006
Lampros, M., Vlachos, N., Zigouris, A., Voulgaris, S. and Alexiou, G.A. (2021) Transcutaneous Vagus Nerve Stimulation (t-VNS) and Epilepsy: A Systematic Review of the Literature. Seizure, 91, 40-48. https://doi.org/10.1016/j.seizure.2021.05.017
Yap, J.Y.Y., Keatch, C., Lambert, E., Woods, W., Stoddart, P.R. and Kameneva, T. (2020) Critical Review of Transcutaneous Vagus Nerve Stimulation: Challenges for Translation to Clinical Practice. Frontiers in Neuroscience, 14, Article 284. https://doi.org/10.3389/fnins.2020.00284
Lanska, D.J. (2002) J.L. Corning and Vagal Nerve Stimulation for Seizures in the 1880s. Neurology, 58, 452-459. https://doi.org/10.1212/WNL.58.3.452
Zabara, J. (1992) Inhibition of Experimental Seizures in Canines by Repetitive Vagal Stimulation. Epilepsia, 33, 1005-1012. https://doi.org/10.1111/j.1528-1157.1992.tb01751.x
Englot, D.J. (2018) A Modern Epilepsy Surgery Treatment Algorithm: Incorporating Traditional and Emerging Technologies. Epilepsy and Behavior, 80, 68-74. https://doi.org/10.1016/j.yebeh.2017.12.041
Englot, D.J., Rolston, J.D., Wright, C.W., Hassnain, K.H. and Chang, E.F. (2016) Rates and Predictors of Seizure Freedom with Vagus Nerve Stimulation for Intractable Epilepsy. Neurosurgery, 79, 345-353. https://doi.org/10.1227/NEU.0000000000001165
Pérez-Carbonell, L., Faulkner, H., Higgins, S., Koutroumanidis, M. and Leschziner, G. (2020) Vagus Nerve Stimulation for Drug-Resistant Epilepsy. Practical Neurology, 20, 189-198. https://doi.org/10.1136/practneurol-2019-002210
Suller Marti, A., Mirsattari, S.M., MacDougall, K., Steven, D.A., Parrent, A., de Ribaupierre, S., et al. (2020) Vagus Nerve Stimulation in Patients with Therapy-Resistant Generalized Epilepsy. Epilepsy and Behavior, 111, Article ID: 107253. https://doi.org/10.1016/j.yebeh.2020.107253
Boluk, C., Ozkara, C., Isler, C. and Uzan, M. (2022) Vagus Nerve Stimulation in Intractable Epilepsy. Turkish Neurosurgery, 32, 97-102. https://doi.org/10.5137/1019-5149.JTN.33775-21.2
Skarpaas, T.L., Jarosiewicz, B. and Morrell, M.J. (2019) Brain-Responsive Neurostimulation for Epilepsy (RNS® System). Epilepsy Research, 153, 68-70. https://doi.org/10.1016/j.eplepsyres.2019.02.003
Heck, C.N., King-Stephens, D., Massey, A.D., Nair, D.R., Jobst, B.C., Barkley, G.L., et al. (2014) Two-Year Seizure Reduction in Adults with Medically Intractable Partial Onset Epilepsy Treated with Responsive Neurostimulation: Final Results of the RNS System Pivotal Trial. Epilepsia, 55, 432-441. https://doi.org/10.1111/epi.12534
Bergey, G.K., Morrell, M.J., Mizrahi, E.M., Goldman, A., King-Stephens, D., Nair, D., et al. (2015) Long-Term Treatment with Responsive Brain Stimulation in Adults with Refractory Partial Seizures. Neurology, 84, 810-817. https://doi.org/10.1212/WNL.0000000000001280
Nair, D.R., Morrell, M.J., Skarpaas, T.L., Murro, A.M., Park, Y.D., Barkley, G.L., et al. (2020) Nine-Year Prospective Efficacy and Safety of Brain-Responsive Neurostimulation for Focal Epilepsy. Neurology, 95, E1244-E1256.
Kusske, J.A., Ojemann, G.A. and Ward, A.A. (1972) Effects of Lesions in Ventral Anterior Thalamus on Experimental Focal Epilepsy. Experimental Neurology, 34, 279-290. https://doi.org/10.1016/0014-4886(72)90174-4
Mirski, M.A. and Ferrendelli, J.A. (1986) Anterior Thalamic Mediation of Generalized Pentylenetetrazol Seizures. Brain Research, 399, 212-223. https://doi.org/10.1016/0006-8993(86)91511-8
Anderson, W.S. (2019) Deep Brain Stimulation: Techniques and Practices. Thieme, Leipzig. https://doi.org/10.1055/b-0039-168471
Fisher, R., Salanova, V., Witt, T., Worth, R., Henry, T., Gross, R., et al. (2010) Electrical Stimulation of the Anterior Nucleus of Thalamus for Treatment of Refractory Epilepsy. Epilepsia, 51, 899-908. https://doi.org/10.1111/j.1528-1167.2010.02536.x
Salanova, V., Witt, T., Worth, R., Henry, T.R., Gross, R.E., Nazzaro, J.M., et al. (2015) Long-Term Efficacy and Safety of Thalamic Stimulation for Drug-Resistant Partial Epilepsy. Neurology, 84, 1017-1025. https://doi.org/10.1212/WNL.0000000000001334
Salanova, V., Sperling, M.R., Gross, R.E., Irwin, C.P., Vollhaber, J.A., Giftakis, J.E., et al. (2021) The SANTÉ Study at 10 Years of Follow-up: Effectiveness, Safety, and Sudden Unexpected Death in Epilepsy. Epilepsia, 62, 1306-1317. https://doi.org/10.1111/epi.16895