Pharmacoresistance occurs in up to 30% of patients with epilepsy, and is most commonly associated with epilepsy of structural or metabolic origin, abnormal findings on brain imaging or examination, and failure to respond to the first two antiepileptic drugs. However, in patients presumed to have difficult to treat epilepsy, factors that might result in apparent treatment resistance (misdiagnosis of epilepsy, incorrect drug and/or dose, and lifestyle issues) must first be excluded and the diagnosis re-examined. Epilepsy is commonly misdiagnosed, especially in patients with syncope and psychogenic events. The initial steps in confirming the diagnoses of both epilepsy and pharmacoresistance are to obtain a detailed, reliable history and to conduct a careful review of all prior trials of antiepileptic drug therapy. Once the diagnoses of epilepsy and pharmacoresistance are confirmed, the seizure type, epilepsy syndrome, and expected course of the disorder dictate its medical and surgical management. Epilepsy surgery should be considered promptly in these patients, since few interventions are as effective as brain surgery in this setting, particularly in patients with focal pharmacoresistant epilepsy. This Review discusses the concept of pharmacoresistance and describes the approach to management of the patient with difficult to treat epilepsy, focusing on the important role of epilepsy surgery.
About 25% of patients identified as having difficult to treat epilepsy do not have pharmacoresistance and/or epilepsy
Pharmacoresistance occurs in up to 30% of patients with epilepsy, and is usually identified after patients fail to respond to two antiepileptic drugs
The diagnosis of pharmacoresistant epilepsy should be confirmed and acted on promptly to control seizures
Surgery is a highly effective treatment for pharmacoresistant epilepsy—65% of patients with pharmacoresistant focal epilepsy achieve sustained seizure remission after surgical therapy
Despite robust evidence of its efficacy and safety, surgical treatment for epilepsy remains underutilized
Your institute does not have access to this article
Open Access articles citing this article.
Pulsed-Focused Ultrasound Provides Long-Term Suppression of Epileptiform Bursts in the Kainic Acid-Induced Epilepsy Rat Model
Neurotherapeutics Open Access 17 May 2022
BMC Neurology Open Access 04 March 2022
Effectiveness, retention, and safety of modified ketogenic diet in adults with epilepsy at a tertiary-care centre in the UK
Journal of Neurology Open Access 10 January 2020
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Annegers, J. F., Hauser, W. A. & Elveback, L. R. Remission of seizures and relapse in patients with epilepsy. Epilepsia 20, 729–737 (1979).
Shafer, S. Q., Hauser, W. A., Annegers, J. F. & Klass, D. W. EEG and other early predictors of epilepsy remission: a community study. Epilepsia 29, 590–600 (1988).
Cockerell, O. C., Johnson, A. L., Sander, J. W., Hart, Y. M. & Shorvon, S. D. Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet 346, 140–144 (1995).
Cockerell, O. C., Johnson, A. L., Sander, J. W. & Shorvon, S. D. Prognosis of epilepsy: a review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study. Epilepsia 38, 31–46 (1997).
Lindsten, H., Stenlund, H. & Forsgren, L. Remission of seizures in a population-based adult cohort with a newly diagnosed unprovoked epileptic seizure. Epilepsia 42, 1025–1030 (2001).
Sillanpaa, M., Jalava, M., Kaleva, O. & Shinnar, S. Long-term prognosis of seizures with onset in childhood. N. Engl. J. Med. 338, 1715–1722 (1998).
Banerjee, P. N., Filippi, D. & Allen Hauser, W. The descriptive epidemiology of epilepsy—a review. Epilepsy Res. 85, 31–45 (2009).
Schuele, S. U. & Lüders, H. O. Intractable epilepsy: management and therapeutic alternatives. Lancet Neurol. 7, 514–524 (2008).
Wiebe, S. & Hesdorffer, D. C. Epilepsy: being ill in more ways than one. Epilepsy Curr. 7, 145–148 (2007).
Hamiwka, L. D. et al. Social outcomes after temporal or extra-temporal epilepsy surgery: a systematic review. Epilepsia 52, 870–879 (2011).
Kwon, C. S. et al. The incidence of injuries in persons with and without epilepsy—a population-based study. Epilepsia 51, 2247–2253 (2010).
Sperling, M. R., Feldman, H., Kinman, J., Liporace, J. D. & O'Connor, M. J. Seizure control and mortality in epilepsy. Ann. Neurol. 46, 45–50 (1999).
Leach, J. P., Lauder, R., Nicolson, A. & Smith, D. F. Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project. Seizure 14, 514–520 (2005).
Hamiwka, L. D., Singh, N., Niosi, J. & Wirrell, E. C. Diagnostic inaccuracy in children referred with “first seizure”: role for a first seizure clinic. Epilepsia 48, 1062–1066 (2007).
Beach, R. & Reading, R. The importance of acknowledging clinical uncertainty in the diagnosis of epilepsy and non-epileptic events. Arch. Dis. Child. 90, 1219–1222 (2005).
Scheepers, B., Clough, P. & Pickles, C. The misdiagnosis of epilepsy: findings of a population study. Seizure 7, 403–406 (1998).
Smith, D., Defalla, B. A. & Chadwick, D. W. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. QJM 92, 15–23 (1999).
Josephson, C. B., Rahey, S. & Sadler, R. M. Neurocardiogenic syncope: frequency and consequences of its misdiagnosis as epilepsy. Can. J. Neurol. Sci. 34, 221–224 (2007).
Uldall, P., Alving, J., Hansen, L. K., Kibaek, M. & Buchholt, J. The misdiagnosis of epilepsy in children admitted to a tertiary epilepsy centre with paroxysmal events. Arch. Dis. Child. 91, 219–221 (2006).
Zaidi, A., Clough, P., Cooper, P., Scheepers, B. & Fitzpatrick, A. P. Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause. J. Am. Coll. Cardiol. 36, 181–184 (2000).
Boesebeck, F., Freermann, S., Kellinghaus, C. & Evers, S. Misdiagnosis of epileptic and non-epileptic seizures in a neurological intensive care unit. Acta Neurol. Scand. 122, 189–195 (2010).
Sarkar, U. et al. Challenges of making a diagnosis in the outpatient setting: a multi-site survey of primary care physicians. BMJ Qual. Saf. http://dx.doi.org/10.1136/bmjqs-2011-000541.
Stephen, L. J. & Brodie, M. J. Antiepileptic drug monotherapy versus polytherapy: pursuing seizure freedom and tolerability in adults. Curr. Opin. Neurol. 25, 164–172 (2012).
Kwan, P., Schachter, S. C. & Brodie, M. J. Drug-resistant epilepsy. N. Engl. J. Med. 365, 919–926 (2011).
Levy, R. G., Cooper, P. N. & Giri, P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD001903. http://dx.doi.org/10.1002/14651858.CD001903.pub2.
Fisher, R. S. Therapeutic devices for epilepsy. Ann. Neurol. 71, 157–168 (2012).
Tellez-Zenteno, J. F., Dhar, R. & Wiebe, S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 128, 1188–1198 (2005).
Wiebe, S. & Jette, N. Epilepsy surgery utilization: who, when, where, and why? Curr. Opin. Neurol. 25, 187–193 (2012).
Wiebe, S. Still an elusive target: guiding practice for epilepsy surgery. Neurology 75, 678–679 (2010).
Engel, J. Jr et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons. Neurology 60, 538–547 (2003).
NHS National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE Clinical Guidelines [online], (2012).
Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults. A national clinical guideline [online], (2003).
Labiner, D. M. et al. Essential services, personnel, and facilities in specialized epilepsy centers—revised 2010 guidelines. Epilepsia 51, 2322–2333 (2010).
Benbadis, S. R. Errors in EEGs and the misdiagnosis of epilepsy: importance, causes, consequences, and proposed remedies. Epilepsy Behav. 11, 257–262 (2007).
Krauss, G. L., Abdallah, A., Lesser, R., Thompson, R. E. & Niedermeyer, E. Clinical and EEG features of patients with EEG wicket rhythms misdiagnosed with epilepsy. Neurology 64, 1879–1883 (2005).
Falip, M., Gil-Nagel, A., Viteri Torres, C. & Gomez-Alonso, J. Diagnostic problems in the initial assessment of epilepsy. Neurologist 13 (Suppl. 1), S2–S10 (2007).
Rugg-Gunn, F. J., Harrison, N. A. & Duncan, J. S. Evaluation of the accuracy of seizure descriptions by the relatives of patients with epilepsy. Epilepsy Res. 43, 193–199 (2001).
Heo, J. H. et al. Reliability of semiology description. Neurologist 14, 7–11 (2008).
Sheldon, R. et al. Historical criteria that distinguish syncope from seizures. J. Am. Coll. Cardiol. 40, 142–148 (2002).
Krumholz, A. et al. Practice parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 69, 1996–2007 (2007).
Aylward, R. L. Epilepsy: a review of reports, guidelines, recommendations and models for the provision of care for patients with epilepsy. Clin. Med. 8, 433–438 (2008).
Yogarajah, M. et al. Long term monitoring in refractory epilepsy: the Gowers Unit experience. J. Neurol. Neurosurg. Psychiatry 80, 305–310 (2009).
Kwan, P. & Brodie, M. J. Early identification of refractory epilepsy. N. Engl. J. Med. 342, 314–319 (2000).
Schiller, Y. & Najjar, Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology 70, 54–65 (2008).
Berg, A. T., Levy, S. R., Testa, F. M. & D'Souza, R. Remission of epilepsy after two drug failures in children: a prospective study. Ann. Neurol. 65, 510–519 (2009).
Sillanpaa, M. & Schmidt, D. Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain 129, 617–624 (2006).
Choi, H. et al. Seizure remission and relapse in adults with intractable epilepsy: a cohort study. Epilepsia 49, 1440–1445 (2008).
Callaghan, B. et al. Remission and relapse in a drug-resistant epilepsy population followed prospectively. Epilepsia 52, 619–626 (2011).
Brodie, M. J., Barry, S. J., Bamagous, G. A., Norrie, J. D. & Kwan, P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 78, 1548–1554 (2012).
Schmidt, D. & Sillanpaa, M. Evidence-based review on the natural history of the epilepsies. Curr. Opin. Neurol. 25, 159–163 (2012).
Kwan, P. et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51, 1069–1077 (2010).
Jette, N. et al. A literature review of the natural history, epidemiology and surgical outcomes of epilepsy, with a focus on localization-related epilepsy [online], (2009).
Berg, A. T. et al. Early development of intractable epilepsy in children: a prospective study. Neurology 56, 1445–1452 (2001).
Ramos-Lizana, J., Aguilera-Lopez, P., Aguirre-Rodriguez, J. & Cassinello-Garcia, E. Early prediction of refractory epilepsy in childhood. Seizure 18, 412–416 (2009).
Semah, F. et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 51, 1256–1262 (1998).
Camfield, P. & Camfield, C. Childhood epilepsy: what is the evidence for what we think and what we do? J. Child. Neurol. 18, 272–287 (2003).
Berg, A. T. et al. Defining early seizure outcomes in pediatric epilepsy: the good, the bad and the in-between. Epilepsy Res. 43, 75–84 (2001).
Casetta, I. et al. Early predictors of intractability in childhood epilepsy: a community-based case–control study in Copparo, Italy. Acta Neurol. Scand. 99, 329–333 (1999).
Brorson, L. O. & Wranne, L. Long-term prognosis in childhood epilepsy: survival and seizure prognosis. Epilepsia 28, 324–330 (1987).
Elwes, R. D., Johnson, A. L., Shorvon, S. D. & Reynolds, E. H. The prognosis for seizure control in newly diagnosed epilepsy. N. Engl. J. Med. 311, 944–947 (1984).
[No authors listed] Prognosis of epilepsy in newly referred patients: a multicenter prospective study of the effects of monotherapy on the long-term course of epilepsy. Collaborative Group for the Study of Epilepsy. Epilepsia 33, 45–51 (1992).
Arts, W. F. et al. The early prognosis of epilepsy in childhood: the prediction of a poor outcome. The Dutch study of epilepsy in childhood. Epilepsia 40, 726–734 (1999).
Altunbasak, S., Herguner, O. & Burgut, H. R. Risk factors predicting refractoriness in epileptic children with partial seizures. J. Child. Neurol. 22, 195–199 (2007).
Gilioli, I. et al. Focal epilepsies in adult patients attending two epilepsy centers: classification of drug-resistance, assessment of risk factors, and usefulness of “new” antiepileptic drugs. Epilepsia 53, 733–740 (2012).
Brodie, M. J. & Kwan, P. Staged approach to epilepsy management. Neurology 58 (Suppl. 5), S2–S8 (2002).
Mohanraj, R. & Brodie, M. J. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur. J. Neurol. 13, 277–282 (2006).
Hitiris, N., Mohanraj, R., Norrie, J., Sills, G. J. & Brodie, M. J. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 75, 192–196 (2007).
Sillanpaa, M. Remission of seizures and predictors of intractability in long-term follow-up. Epilepsia 34, 930–936 (1993).
Hauser, E., Freilinger, M., Seidl, R. & Groh, C. Prognosis of childhood epilepsy in newly referred patients. J. Child. Neurol. 11, 201–204 (1996).
Holowach, J., Thurston, D. L. & O'Leary, J. Prognosis in childhood epilepsy. Follow-up study of 148 cases in which therapy had been suspended after prolonged anticonvulsant control. N. Engl. J. Med. 286, 169–174 (1972).
Shorvon, S. D. & Reynolds, E. H. Early prognosis of epilepsy. Br. Med. J. (Clin. Res. Ed.) 285, 1699–1701 (1982).
Stephen, L. J., Kwan, P. & Brodie, M. J. Does the cause of localisation-related epilepsy influence the response to antiepileptic drug treatment? Epilepsia 42, 357–362 (2001).
Dlugos, D. J. The early identification of candidates for epilepsy surgery. Arch. Neurol. 58, 1543–1546 (2001).
Callaghan, B. C., Anand, K., Hesdorffer, D., Hauser, W. A. & French, J. A. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann. Neurol. 62, 382–389 (2007).
Spooner, C. G., Berkovic, S. F., Mitchell, L. A., Wrennall, J. A. & Harvey, A. S. New-onset temporal lobe epilepsy in children: lesion on MRI predicts poor seizure outcome. Neurology 67, 2147–2153 (2006).
Schmidt, D., Baumgartner, C. & Loscher, W. The chance of cure following surgery for drug-resistant temporal lobe epilepsy: what do we know and do we need to revise our expectations? Epilepsy Res. 60, 187–201 (2004).
Schmidt, D. & Loscher, W. How effective is surgery to cure seizures in drug-resistant temporal lobe epilepsy? Epilepsy Res. 56, 85–91 (2003).
Tellez-Zenteno, J. F. et al. Discontinuation of antiepileptic drugs after successful epilepsy surgery. A Canadian survey. Epilepsy Res. http://dx.doi.org/10.1016/j.eplepsyres.2012.04.018.
Duncan, J. S. Imaging in the surgical treatment of epilepsy. Nat. Rev. Neurol. 6, 537–550 (2010).
Blanco, J. A. et al. Data mining neocortical high-frequency oscillations in epilepsy and controls. Brain 134, 2948–2959 (2011).
Andrade-Valenca, L. P., Dubeau, F., Mari, F., Zelmann, R. & Gotman, J. Interictal scalp fast oscillations as a marker of the seizure onset zone. Neurology 77, 524–531 (2011).
Jacobs, J. et al. High-frequency electroencephalographic oscillations correlate with outcome of epilepsy surgery. Ann. Neurol. 67, 209–220 (2010).
Tellez-Zenteno, J. F., Dhar, R., Hernandez-Ronquillo, L. & Wiebe, S. Long-term outcomes in epilepsy surgery: antiepileptic drugs, mortality, cognitive and psychosocial aspects. Brain 130, 334–345 (2007).
Wiebe, S., Blume, W. T., Girvin, J. P. & Eliasziw, M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345, 311–318 (2001).
Engel, J. Jr et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 307, 922–930 (2012).
de Tisi, J. et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 378, 1388–1395 (2011).
Englot, D. J., Ouyang, D., Garcia, P. A., Barbaro, N. M. & Chang, E. F. Epilepsy surgery trends in the United States, 1990–2008. Neurology 78, 1200–1206 (2012).
Haneef, Z., Stern, J., Dewar, S., Engel, J. Jr. Referral pattern for epilepsy surgery after evidence-based recommendations: a retrospective study. Neurology 75, 699–704 (2010).
Uijl, S. G. et al. Epilepsy surgery can help many more adult patients with intractable seizures. Epilepsy Res. http://dx.doi.org/10.1016/j.eplepsyres.2012.04.002.
de Flon, P., Kumlien, E., Reuterwall, C. & Mattsson, P. Empirical evidence of underutilization of referrals for epilepsy surgery evaluation. Eur. J. Neurol. 17, 619–625 (2010).
Bell, G. S. et al. Premature mortality in refractory partial epilepsy: does surgical treatment make a difference? J. Neurol. Neurosurg. Psychiatry 81, 716–718 (2010).
Choi, H. et al. Epilepsy surgery for pharmacoresistant temporal lobe epilepsy: a decision analysis. JAMA 300, 2497–2505 (2008).
Seiam, A. H., Dhaliwal, H. & Wiebe, S. Determinants of quality of life after epilepsy surgery: systematic review and evidence summary. Epilepsy Behav. 21, 441–445 (2011).
Macrodimitris, S. et al. Psychiatric outcomes of epilepsy surgery: a systematic review. Epilepsia 52, 880–890 (2011).
Sherman, E. M. et al. Neuropsychological outcomes after epilepsy surgery: systematic review and pooled estimates of cognitive change. Epilepsia 52, 857–869 (2011).
Langfitt, J. T. et al. Worsening of quality of life after epilepsy surgery: effect of seizures and memory decline. Neurology 68, 1988–1994 (2007).
Macrodimitris, S., Sherman, E. M., Williams, T. S., Bigras, C. & Wiebe, S. Measuring patient satisfaction following epilepsy surgery. Epilepsia 52, 1409–1417 (2011).
Tellez-Zenteno, J. F., Hernandez Ronquillo, L., Moien-Afshari, F. & Wiebe, S. Surgical outcomes in lesional and non-lesional epilepsy: a systematic review and meta-analysis. Epilepsy Res. 89, 310–318 (2010).
Hong, S. C. et al. Surgical treatment of intractable epilepsy accompanying cortical dysplasia. J. Neurosurg. 93, 766–773 (2000).
Tonini, C. et al. Predictors of epilepsy surgery outcome: a meta-analysis. Epilepsy Res. 62, 75–87 (2004).
McIntosh, A. M., Kalnins, R. M., Mitchell, L. A. & Berkovic, S. F. Early seizures after temporal lobectomy predict subsequent seizure recurrence. Ann. Neurol. 57, 283–288 (2005).
Schmidt, D., Baumgartner, C. & Loscher, W. Seizure recurrence after planned discontinuation of antiepileptic drugs in seizure-free patients after epilepsy surgery: a review of current clinical experience. Epilepsia 45, 179–186 (2004).
Salanova, V., Markand, O. & Worth, R. Temporal lobe surgery: analysis of failures and the role of reoperation. Acta Neurol. Scand. 111, 126–133 (2005).
Awad, I. A., Nayel, M. H. & Lüders, H. Second operation after failure of previous resection for epilepsy. Neurosurgery 28, 510–518 (1991).
S. Wiebe has received grants from the Canadian Institutes of Health Research, the National Institutes of Neurological Disorders and Stroke, the Public Health Agency of Canada, Alberta Innovates Health Solutions, Alberta Health Services, the University of Calgary Faculty of Medicine and Hotchkiss Brain Institute. N. Jette holds a Population Health Investigator Award from Alberta Innovates Health Solutions and a Canada Research Chair Tier 2 in Neuroscience Health Services Research. She has received grants or research support from the Canadian Institutes of Health Research, the Public Health Agency of Canada, Alberta Innovates Health Solutions, Alberta Health Services, the University of Calgary Faculty of Medicine and Hotchkiss Brain Institute and Alberta Health and Wellness. The authors thank Dr Elaine Wirrell for giving permission to use some of her data from a literature review written with N. Jette on predictors of remission and intractability in patients with epilepsy.
The authors declare no competing financial interests.
About this article
Cite this article
Wiebe, S., Jette, N. Pharmacoresistance and the role of surgery in difficult to treat epilepsy. Nat Rev Neurol 8, 669–677 (2012). https://doi.org/10.1038/nrneurol.2012.181
BMC Neurology (2022)
Journal of Neurology (2022)
Recent investigation on heterocycles with one nitrogen [piperidine, pyridine and quinoline], two nitrogen [1,3,4-thiadiazole and pyrazole] and three nitrogen [1,2,4-triazole]: a review
Journal of the Iranian Chemical Society (2022)
Pulsed-Focused Ultrasound Provides Long-Term Suppression of Epileptiform Bursts in the Kainic Acid-Induced Epilepsy Rat Model
CNS Drugs (2022)