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Long-term outcomes of surgical treatment for epilepsy in adults with regard to seizures, antiepileptic drug treatment and employment

  • Kristina Malmgren
    Correspondence
    Corresponding author at: Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University and Sahlgrenska University Hospital, Blå Stråket 7, 3rd Floor, SE 413 45 Gothenburg, Sweden.
    Affiliations
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • Anna Edelvik
    Affiliations
    Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University and Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Open ArchivePublished:October 21, 2016DOI:https://doi.org/10.1016/j.seizure.2016.10.015

      Highlights

      • Long-term seizure freedom in adults since temporal lobe resection is around 50%.
      • A higher proportion has been seizure-free at least a year at each time-point assessed.
      • Proportion seizure-free off anti-epileptic drugs long-term after surgery varies.
      • Long-term employment outcomes are not consistent across studies.

      Abstract

      Purpose

      There is Class I evidence for short-term efficacy of epilepsy surgery from two randomized controlled studies of temporal lobe resection. Long-term outcome studies are observational. The aim of this narrative review was to summarise long-term outcomes taking the study methodology into account.

      Methods

      A PubMed search was conducted identifying articles on long-term outcomes of epilepsy surgery in adults with regard to seizures, antiepileptic drug treatment and employment. Definitions of seizure freedom were examined in order to identify the proportions of patients with sustained seizure freedom. The quality of the long-term studies was assessed.

      Results

      In a number of high-quality studies 40–50% of patients had been continuously free from seizures with impairment of consciousness 10 years after resective surgery, with a higher proportion seizure-free at each annual follow-up. The proportion of seizure-free adults in whom AEDs have been withdrawn varied widely across studies, from 19–63% after around 5 years of seizure freedom. Few long-term vocational outcome studies were identified and results were inconsistent. Some investigators found no postoperative changes, others found decreased employment for patients with continuing seizures, but no change or increased employment for seizure-free patients. Having employment at baseline and postoperative seizure freedom were the strongest predictors of employment after surgery.

      Conclusions

      Long-term studies of outcomes after epilepsy surgery are by necessity observational. There is a need for more prospective longitudinal studies of both seizure and non-seizure outcomes, considering individual patient trajectories in order to obtain valid outcome data needed for counselling patients about epilepsy surgery.

      Keywords

      1. Introduction

      Surgical treatment for epilepsy has long been recognized as a valuable treatment option for carefully selected patients with drug-resistant focal epilepsy. In adults most operations are temporal lobe resections (TLR), and there is Class I evidence for the short-term efficacy (1 and 2 years follow-up respectively) from two randomized controlled studies (RCTs) of TLR [
      • Wiebe S.
      • Blume W.T.
      • Girvin J.P.
      • Eliasziw M.
      A randomized, controlled trial of surgery for temporal-lobe epilepsy.
      ,
      • Engel Jr., J.
      • McDermott M.P.
      • Wiebe S.
      • Langfitt J.T.
      • Stern J.M.
      • Dewar S.
      • et al.
      Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial.
      ]. Smaller numbers of patients undergo frontal lobe resections (FLR) or other extratemporal resections [
      • Tellez-Zenteno J.F.
      • Dhar R.
      • Wiebe S.
      Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis.
      ]. Very few adults undergo hemispherectomies [
      • Schramm J.
      • Delev D.
      • Wagner J.
      • Elger C.E.
      • von Lehe M.
      Seizure outcome, functional outcome, and quality of life after hemispherectomy in adults.
      ]. In some patients palliative procedures such as callosotomy or other dissociative procedures may be indicated when resective surgery is not an option [
      • Park M.S.
      • Nakagawa E.
      • Schoenberg M.R.
      • Benbadis S.R.
      • Vale F.L.
      Outcome of corpus callosotomy in adults.
      ]. There are no RCTs for any of these surgical treatments.
      The neurosurgical advances in epilepsy surgery develop toward minimally invasive techniques, with the ultimate aim to improve or maintain efficacy while reducing adverse effects. These techniques include radiofrequency thermocoagulation, MR-guided focused ultrasound, laser ablation and stereotactic radiosurgery [
      • Nowell M.
      • Miserocchi A.
      • McEvoy A.W.
      • Duncan J.S.
      Advances in epilepsy surgery.
      ]. There are as yet no prospective long-term reports of efficacy and safety for these new epilepsy treatments, the outcomes of which are therefore not addressed in this review. Palliative procedures (e.g., callosotomy) are not considered either due to the scarcity of long-term follow-up studies.
      Until recently the knowledge about seizure outcomes after epilepsy surgery procedures was mainly based on short-term follow-ups (1–2 years). Epilepsy surgery candidates, however, are mostly young adults, and as well as information about the short-term chances of seizure control versus risks (complications as well as expected adverse effects), they need detailed advice about likely long-term seizure outcome before deciding to undergo brain surgery.
      Patients’ aims for epilepsy surgery are not limited to seizure relief. To be able to stop antiepileptic drugs (AEDs) and to be employed (or when employed, to be able to work more than preoperatively) are among the most important of these aims [
      • Taylor D.C.
      • McMacKin D.
      • Staunton H.
      • Delanty N.
      • Phillips J.
      Patients’ aims for epilepsy surgery: desires beyond seizure freedom.
      ,
      • Wilson S.J.
      • Saling M.M.
      • Kincade P.
      • Bladin P.F.
      Patient expectations of temporal lobe surgery.
      ]. Realistic expectations concerning long-term seizure, employment and AED outcomes are therefore part of the information they need to consider.
      Long-term outcome studies are by necessity observational since RCTs would be unfeasible as well as unethical. However, observational studies have methodological limitations which are also incorporated in systematic reviews of epilepsy surgery outcomes. In order to compare data from different observational studies, defined quality criteria are needed and a number of requirements for well-conducted studies on the prognosis after epilepsy surgery have been suggested: e.g., prospective study design, representative/population-based study populations, large enough cohorts, well defined inclusion criteria, satisfactory and complete follow-up, longitudinal follow-ups, masked assessment of outcome, clearly defined outcomes, adequate statistical methods and standard definition of prognostic factors [
      • Beghi E.
      • Tonini C.
      Surgery for epilepsy: assessing evidence from observational studies.
      ,
      • Beghi E.
      Methodological demands on observational studies of outcomes after epilepsy surgery.
      ]. When reviewing the literature we have focused on studies which as far as possible fulfill these requirements.
      The aim of this review is to focus on outcomes from epilepsy surgery regarding seizures, antiepileptic drug treatment and employment in adults beyond at least a 4-year time period following surgery.

      2. Search strategy and selection criteria

      For this review we performed a PubMed search without date limits or restriction on type of articles, but with language restrictions to English only.
      The following search terms were used in various combinations: “epilepsy surgery” (4153 results) “long-term”, outcome*, “antiepileptic drug*”, employment, vocational, psychosocial. Titles that clearly indicated e.g., only pediatric populations, non-surgical series, case reports, non-resective procedures and vagus nerve stimulation were not considered further.
      For long-term seizure outcomes, the search string “epilepsy surgery” AND “long-term” AND “outcome*” resulted in 348 references, 196 of which were further assessed by reading the abstracts and 95 by screening the full text. For long-term outcomes of AED treatment “epilepsy surgery” AND “antiepileptic drug*” resulted in 200 references, where 31 were assessed by reading the abstracts and 18 in full text. For employment outcomes “epilepsy surgery” AND (employment OR vocational OR psychosocial) yielded 143 titles; 57 were assessed by reading the abstracts and 30 in full text. In addition, reference lists of reviews or meta-analyses were checked for additional articles missed in the electronic search.

      3. Reporting of seizure outcomes

      When assessing the literature on seizure outcomes after epilepsy surgery it has to be considered that seizure outcome and seizure freedom is not consistently defined. The most commonly used scheme is the Engel classification with one original and one revised version [
      • Engel J.
      Outcome with respect to epileptic seizures.
      ,
      • Engel J.
      • Van Ness P.C.
      • Rasmussen T.B.
      • Ojemann L.M.
      Outcome with respect to epileptic seizures.
      ], another is the International League Against Epilepsy (ILAE) outcome scale [
      • Wieser H.G.
      • Blume W.T.
      • Fish D.
      • Goldensohn E.
      • Hufnagel A.
      • King D.
      • et al.
      ILAE Commission Report. Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery.
      ]. While part of the Engel classification (class I A and I B) takes account of the whole postoperative period, the ILAE classification refers to the seizure outcome the last year of follow-up and the seizure outcome class should be determined for each year at annual intervals after surgery. However, both classifications make it possible to identify patients who have been completely seizure free without auras since the operation (Engel class I A, and ILAE class 1a). In the original Engel classification class I B identifies those patients who have had auras only but no seizures with impairment of consciousness since surgery while the revised version accepts all non-disabling simple partial seizures for a class I B categorization. Both the Engel and the ILAE classifications exclude early postoperative seizures.
      Many studies report seizure outcome the last year of follow-up and do not distinguish patients who have been seizure free since surgery, although this is the most important patient group to identify in order to advise surgical candidates about their chances of good outcome. Seizure freedom is most often defined as freedom from seizures with impairment of consciousness, or Engel I (which also includes class I C, i.e., patients who have had some seizures with impairment of consciousness after surgery but then been seizure free at least two years and class I D, i.e., patients who have had secondary generalized convulsive seizures on AED withdrawal). Some studies differentiate into completely seizure-free (Engel I A or ILAE Class 1a) or include patients with auras only in the category of seizure free (Engel I A and B or ILAE Class 1a and 2). Although both scales include a possibility to note worsening of seizure frequency postoperatively, this is seldom reported.

      4. Long-term seizure outcomes

      During the last decade an increasing number of epilepsy surgery centers have reported long-term outcomes in cohorts of patients following a variety of surgical interventions. The studies which best fulfill at least four of the above-mentioned criteria for well-conducted studies [
      • Beghi E.
      • Tonini C.
      Surgery for epilepsy: assessing evidence from observational studies.
      ,
      • Beghi E.
      Methodological demands on observational studies of outcomes after epilepsy surgery.
      ] have been summarized in Table 1.
      Table 1Selected high-quality studies fullfilling criteria for well conducted outcome studies.
      Author, yearStudy designNumber in study groupType of surgeryLesion type (histology)Outcome measure5 year outcome %10 year outcome %
      Asztely, 2007P S X65RES, T + XTAllILAE 1 + 258
      Aull-Watschinger, 2008P S L72RES, THSILAE 1a46
      ILAE 1 + 279
      de Tisi, 2011R S L234 at 5 years, 122 at 10 yearsAll (but only 7 NRES)AllILAE 1 + 2 sustained5247
      Edelvik, 2013P N L190RES, T + XTAllILAE 1 + 2 sustained41
      ILAE 1 + 262
      Elsharkawy, 2008R S L66 at 5 years, 31 at 10 yearsRES, FAllEngel I A3535
      Engel I4742
      Elsharkawy, 2009R S L419 at 5 years, 366 at 10 yearsRES, TAllEngel I7171
      Fauser, 2015R S L211, ∼97 at 5 yearsRES, T + XTFCDEngel IA53
      Engel I64
      Jeha, 2007R S L22 at 5 yearsRES, FAllEngel I27
      Luyken, 2003R S C180 at 5 years, 67 at 10 yearsRES, T + XTTumorsEngel I8181
      McIntosh, 2004R S L138 at 5 years, 56 at 10 yearsRES, TAllEngel I A + B + D4841
      McIntosh, 2012R S L81RES, XTAllEngel I A + B14
      ILAE 1 + 237
      Paglioli, 2004P S L135, 69 at 5 yearsRES, THSEngel I A75
      Engel I91
      Spencer, 2005P M X339RES, T + XTAllAt least two years seizure remission, allowing auras69
      Sperling, 1996R S L89RES,TAllAt least one year seizure remission, allowing auras70
      Abbreviations: Study design: P: prospective, R: retrospective, S: single center, N: national (population based), M: multi center, X: cross-sectional, L: longitudinal. Type of surgery: RES: resective surgery, NRES: non-resective surgery, T: temporal lobe, XT: extra-temporal lobes, F: frontal lobe. Lesion type: HS: hippocampal sclerosis, FCD: focal cortical dysplasia. Outcome measure: Sustained: continuous seizure freedom since surgery.
      Long-term outcome after resective epilepsy surgery is often reported cross-sectionally, which makes it difficult to discern temporal trends. In a meta-analysis from 2005 based on 78 studies, 66% of TLR patients, 46% of patients who had parietal or occipital resections (P/OLR) and 27% of FLR patients were seizure-free at follow-up ≥five years post-surgery, but the authors point out that few studies reported sustained seizure freedom from surgery, most report seizure status last year of follow-up and cross-sectionally. Almost all studies described patient cohorts without controls [
      • Tellez-Zenteno J.F.
      • Dhar R.
      • Wiebe S.
      Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis.
      ].
      Several recent studies with prospectively collected long-term data on seizure outcome have provided better information about the chances of sustained seizure freedom. In the largest of these, which is a single-center study of 1160 patients (adults and children) with a cross-sectional follow-up of at least two years (mean follow-up 5.4 years, range 2.0–20.5 years), 50.5% were continuously seizure-free without auras [
      • Bien C.G.
      • Raabe A.L.
      • Schramm J.
      • Becker A.
      • Urbach H.
      • Elger C.E.
      Trends in presurgical evaluation and surgical treatment of epilepsy at one centre from 1988–2009.
      ]. In another single center longitudinal follow-up of 615 adults, 52% of all patients remained free from seizures with impairment of consciousness from the time of surgery (using an outcome classification which equals Engel I A and B) five years after surgery and 47% at ten years [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ]. In a population based national study of 278 patients who had 5 or 10 year follow-up 190 were adults [
      • Edelvik A.
      • Rydenhag B.
      • Olsson I.
      • Flink R.
      • Kumlien E.
      • Kallen K.
      • et al.
      Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
      ]. This study had a control group of 80 adults who had been presurgically evaluated but not had surgery. At long-term 41% of the operated adults had sustained seizure freedom (Engel I A and B [
      • Engel J.
      Outcome with respect to epileptic seizures.
      ]) since surgery, compared to none of the controls.

      4.1 Long-term seizure outcome after temporal lobe resections

      A number of recent longitudinal long-term outcome studies report sustained seizure freedom after TLR. Most are retrospective single center series, only a few are prospective. Sustained seizure freedom is reported as Engel I [
      • Cohen-Gadol A.A.
      • Wilhelmi B.G.
      • Collignon F.
      • White J.B.
      • Britton J.W.
      • Cambier D.M.
      • et al.
      Long-term outcome of epilepsy surgery among 399 patients with nonlesional seizure foci including mesial temporal lobe sclerosis.
      ,
      • McIntosh A.M.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Briellmann R.S.
      • Berkovic S.F.
      Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.
      ], Engel I A [
      • Dupont S.
      • Tanguy M.L.
      • Clemenceau S.
      • Adam C.
      • Hazemann P.
      • Baulac M.
      Long-term prognosis and psychosocial outcomes after surgery for MTLE.
      ,
      • Sindou M.
      • Guenot M.
      • Isnard J.
      • Ryvlin P.
      • Fischer C.
      • Mauguiere F.
      Temporo-mesial epilepsy surgery: outcome and complications in 100 consecutive adult patients.
      ] or Engel I A and B [
      • Paglioli E.
      • Palmini A.
      • da Costa J.C.
      • Portuguez M.
      • Martinez J.V.
      • Calcagnotto M.E.
      • et al.
      Survival analysis of the surgical outcome of temporal lobe epilepsy due to hippocampal sclerosis.
      ] and in a few studies as ILAE class 1 and 2 [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ,
      • Aull-Watschinger S.
      • Pataraia E.
      • Czech T.
      • Baumgartner C.
      Outcome predictors for surgical treatment of temporal lobe epilepsy with hippocampal sclerosis.
      ]. The proportion of patients with sustained seizure freedom around five years postoperatively varies between 44–55% [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ,
      • Edelvik A.
      • Rydenhag B.
      • Olsson I.
      • Flink R.
      • Kumlien E.
      • Kallen K.
      • et al.
      Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
      ,
      • McIntosh A.M.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Briellmann R.S.
      • Berkovic S.F.
      Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.
      ,
      • Dupont S.
      • Tanguy M.L.
      • Clemenceau S.
      • Adam C.
      • Hazemann P.
      • Baulac M.
      Long-term prognosis and psychosocial outcomes after surgery for MTLE.
      ,
      • Aull-Watschinger S.
      • Pataraia E.
      • Czech T.
      • Baumgartner C.
      Outcome predictors for surgical treatment of temporal lobe epilepsy with hippocampal sclerosis.
      ] and 60–80% [
      • Cohen-Gadol A.A.
      • Wilhelmi B.G.
      • Collignon F.
      • White J.B.
      • Britton J.W.
      • Cambier D.M.
      • et al.
      Long-term outcome of epilepsy surgery among 399 patients with nonlesional seizure foci including mesial temporal lobe sclerosis.
      ,
      • Sindou M.
      • Guenot M.
      • Isnard J.
      • Ryvlin P.
      • Fischer C.
      • Mauguiere F.
      Temporo-mesial epilepsy surgery: outcome and complications in 100 consecutive adult patients.
      ,
      • Paglioli E.
      • Palmini A.
      • da Costa J.C.
      • Portuguez M.
      • Martinez J.V.
      • Calcagnotto M.E.
      • et al.
      Survival analysis of the surgical outcome of temporal lobe epilepsy due to hippocampal sclerosis.
      ,
      • Jeha L.E.
      • Najm I.M.
      • Bingaman W.E.
      • Khandwala F.
      • Widdess-Walsh P.
      • Morris H.H.
      • et al.
      Predictors of outcome after temporal lobectomy for the treatment of intractable epilepsy.
      ]. Among the studies with more moderate rates of sustained seizure freedom three of five are prospective [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ,
      • Edelvik A.
      • Rydenhag B.
      • Olsson I.
      • Flink R.
      • Kumlien E.
      • Kallen K.
      • et al.
      Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
      ,
      • Aull-Watschinger S.
      • Pataraia E.
      • Czech T.
      • Baumgartner C.
      Outcome predictors for surgical treatment of temporal lobe epilepsy with hippocampal sclerosis.
      ]. All studies reporting higher rates of sustained seizure freedom were retrospective. A few studies report longitudinal follow-up until 10 years. In one retrospective single center study in 325 patients (adults and children), 48% were continuously seizure free (defined as Engel I A, B and D) after five years and 41% after 10 years [
      • McIntosh A.M.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Briellmann R.S.
      • Berkovic S.F.
      Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.
      ]. In the earlier mentioned study of 615 adults 497 had TLR and 55% of them were seizure free (without or with auras) after five years and 49% after 10 years [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ].
      TLR constitute the majority of resective epilepsy surgery procedures in adults. It is therefore not surprising that most of the long-term outcome studies and especially those presenting longitudinal outcome data using survival methods concern TLR. It is possible to study the long-term prognosis in this more homogenous group of patients. Many factors may influence seizure outcomes e.g., referral bias, epilepsy center experience and resources, time period and histopathology. Fig. 1 illustrates a survival analysis with data from three large centers of time to first seizure (defined as seizures with impairment of consciousness) in adult patients (18 and older) who have undergone any variety of TLR and in whom the main histopathology was mesial sclerosis.
      Fig. 1
      Fig. 1Kaplan–Meier curve for continuous seizure freedom (allowing auras) after temporal lobe resection for hippocampal sclerosis.
      (Reprinted with permission from Springer: Eds Malmgren et al., Long-term Outcomes of Epilepsy Surgery in Adults and Children, Springer, Switzerland 2015, Malmgren et al. [
      • Malmgren K.
      • Baxendale S.
      • Cross J.H.
      Long-term outcomes of epilepsy surgery in adults and children.
      ], Fig. 3.1)
      Data from three large epilepsy surgery centers: Austin Health, Melbourne, Australia (courtesy of Drs A. McIntosh and S. Berkovic), Jefferson Comprehensive Epilepsy Centre, Philadelphia, USA (courtesy of Drs A. Asadi-Pooya and M. Sperling) and UCL, London, U.K. (courtesy of Dr J.S Duncan). The data from UCL were collected at each anniversary after surgery, hence the step-wise appearance of the curve.
      Most relapses were seen in the first five years after which there was some flattening of the gradient. The similarity between the curves from three large single center series from three continents indicates that although factors such as referral or selection bias and differences in presurgical evaluation or surgical procedures may influence outcomes, there seem to be common underlying risks for relapse. It has recently been suggested that temporal plus epilepsy is a major determinant of TLR failures. In a retrospective study from two large centers, 168 patients were included who had TLR of whom 78% had mesial sclerosis. The mean follow-up was 7 years with a minimum of 2 years and the risk of TLR failure was 5.06 (95% CI: 2.36–10.382) greater in patients with temporal plus epilepsy than in those with unilateral temporal lobe epilepsy [
      • Barba C.
      • Rheims S.
      • Minotti L.
      • Guenot M.
      • Hoffmann D.
      • Chabardes S.
      • et al.
      Temporal plus epilepsy is a major determinant of temporal lobe surgery failures.
      ].

      4.2 Long-term seizure outcome after frontal lobe and other extratemporal resections

      In a recent systematic review of long-term outcomes after FLR, the authors identified 21 articles from 1991 to 2010 containing data from 1199 patients (adults and children) with a mean or median follow-up of at least 4 years [
      • Englot D.J.
      • Wang D.D.
      • Rolston J.D.
      • Shih T.T.
      • Chang E.F.
      Rates and predictors of long-term seizure freedom after frontal lobe epilepsy surgery: a systematic review and meta-analysis.
      ]. All studies were retrospective or prospective single center series and the seizure free rates at long term varied from 20% to 78% across individual studies with no significant trend toward better outcomes over time. The overall rate of postoperative seizure freedom reported as Engel I was 45%. The seizure outcome at five years defined as Engel I in the only two studies that provided longitudinal data were 47% and 27% respectively [
      • Elsharkawy A.E.
      • Alabbasi A.H.
      • Pannek H.
      • Schulz R.
      • Hoppe M.
      • Pahs G.
      • et al.
      Outcome of frontal lobe epilepsy surgery in adults.
      ,
      • Jeha L.E.
      • Najm I.
      • Bingaman W.
      • Dinner D.
      • Widdess-Walsh P.
      • Luders H.
      Surgical outcome and prognostic factors of frontal lobe epilepsy surgery.
      ].
      In a few of the studies published after 2010 the reports of long-term outcomes in patients after FLR or other extratemporal resections include information on sustained seizure freedom since surgery. Five years postoperatively these proportions range from 14.7% (Engel I) [
      • McIntosh A.M.
      • Averill C.A.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Jackson G.D.
      • et al.
      Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery.
      ], 27% (Engel I) [
      • Jeha L.E.
      • Najm I.
      • Bingaman W.
      • Dinner D.
      • Widdess-Walsh P.
      • Luders H.
      Surgical outcome and prognostic factors of frontal lobe epilepsy surgery.
      ], 35% after FLR and 33% in other extratemporal resections (Engel I A and B) [
      • Edelvik A.
      • Rydenhag B.
      • Olsson I.
      • Flink R.
      • Kumlien E.
      • Kallen K.
      • et al.
      Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
      ] to 47% (Engel I, 34.8% Engel I A) [
      • Elsharkawy A.E.
      • Alabbasi A.H.
      • Pannek H.
      • Schulz R.
      • Hoppe M.
      • Pahs G.
      • et al.
      Outcome of frontal lobe epilepsy surgery in adults.
      ]. In one cross-sectional FLR study with a mean of six years follow-up 24% were reported to have sustained seizure freedom (Engel I A) [
      • Lazow S.P.
      • Thadani V.M.
      • Gilbert K.L.
      • Morse R.P.
      • Bujarski K.A.
      • Kulandaivel K.
      • et al.
      Outcome of frontal lobe epilepsy surgery.
      ].
      The widely varying long-term seizure outcome after extratemporal resections may in part be due to varying histopathological diagnoses; seizure freedom rates range from 14% at five years (Engel I A and B) [
      • McIntosh A.M.
      • Averill C.A.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Jackson G.D.
      • et al.
      Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery.
      ] (mostly patients with focal cortical dysplasia) to 55% at five years (Engel I) [
      • Hanakova P.
      • Brazdil M.
      • Novak Z.
      • Hemza J.
      • Chrastina J.
      • Oslejskova H.
      • et al.
      Long-term outcome and predictors of resective surgery prognosis in patients with refractory extratemporal epilepsy.
      ] and 52% at 10 years (Engel I, mostly patients with lesional etiology) [
      • Elsharkawy A.E.
      • Behne F.
      • Oppel F.
      • Pannek H.
      • Schulz R.
      • Hoppe M.
      • et al.
      Long-term outcome of extratemporal epilepsy surgery among 154 adult patients.
      ].

      5. Predictors of long-term seizure outcomes after resective epilepsy surgery

      The following prognostic factors have consistently been found to be associated with a better short-term post-surgical seizure outcome: an abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography (EEG), history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection and presence of unilateral interictal spikes [
      • Tonini C.
      • Beghi E.
      • Berg A.T.
      • Bogliun G.
      • Giordano L.
      • Newton R.W.
      • et al.
      Predictors of epilepsy surgery outcome: a meta-analysis.
      ,
      • West S.
      • Nolan S.J.
      • Newton R.
      Surgery for epilepsy: a systematic review of current evidence.
      ]. Several investigators have looked for predictors for seizure freedom (positive) or seizure recurrence (negative) also at long-term (at least four years). While some found no remaining predictors in multivariate analysis [
      • Dupont S.
      • Tanguy M.L.
      • Clemenceau S.
      • Adam C.
      • Hazemann P.
      • Baulac M.
      Long-term prognosis and psychosocial outcomes after surgery for MTLE.
      ,
      • Aull-Watschinger S.
      • Pataraia E.
      • Czech T.
      • Baumgartner C.
      Outcome predictors for surgical treatment of temporal lobe epilepsy with hippocampal sclerosis.
      ,
      • Lazow S.P.
      • Thadani V.M.
      • Gilbert K.L.
      • Morse R.P.
      • Bujarski K.A.
      • Kulandaivel K.
      • et al.
      Outcome of frontal lobe epilepsy surgery.
      ], others have identified a number of predictors. Commonly identified predictors for seizure freedom or “good outcome” are positive MRI and histopathology (varying depending on types of pathology included in analysis) [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ,
      • Edelvik A.
      • Rydenhag B.
      • Olsson I.
      • Flink R.
      • Kumlien E.
      • Kallen K.
      • et al.
      Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
      ,
      • Cohen-Gadol A.A.
      • Wilhelmi B.G.
      • Collignon F.
      • White J.B.
      • Britton J.W.
      • Cambier D.M.
      • et al.
      Long-term outcome of epilepsy surgery among 399 patients with nonlesional seizure foci including mesial temporal lobe sclerosis.
      ,
      • McIntosh A.M.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Briellmann R.S.
      • Berkovic S.F.
      Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.
      ,
      • Jeha L.E.
      • Najm I.
      • Bingaman W.
      • Dinner D.
      • Widdess-Walsh P.
      • Luders H.
      Surgical outcome and prognostic factors of frontal lobe epilepsy surgery.
      ,
      • McIntosh A.M.
      • Averill C.A.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Jackson G.D.
      • et al.
      Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery.
      ,
      • Rathore C.
      • Panda S.
      • Sarma P.S.
      • Radhakrishnan K.
      How safe is it to withdraw antiepileptic drugs following successful surgery for mesial temporal lobe epilepsy?.
      ,
      • Luyken C.
      • Blumcke I.
      • Fimmers R.
      • Urbach H.
      • Elger C.E.
      • Wiestler O.D.
      • et al.
      The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.
      ]. Positive predictors in patients at least four years after FLR were lesional epilepsy, abnormal MRI, localized resection as opposed to more extensive frontal or multilobar resections [
      • Englot D.J.
      • Wang D.D.
      • Rolston J.D.
      • Shih T.T.
      • Chang E.F.
      Rates and predictors of long-term seizure freedom after frontal lobe epilepsy surgery: a systematic review and meta-analysis.
      ]. In lesional cases, gross-total resection (as opposed to subtotal resection) led to better seizure outcome.
      Several factors have been identified as predictors negatively related with long-term seizure freedom: generalized convulsive seizures at baseline [
      • McIntosh A.M.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Briellmann R.S.
      • Berkovic S.F.
      Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence.
      ,
      • Spencer S.S.
      • Berg A.T.
      • Vickrey B.G.
      • Sperling M.R.
      • Bazil C.W.
      • Shinnar S.
      • et al.
      Predicting long-term seizure outcome after resective epilepsy surgery: the multicenter study.
      ,
      • Schwartz T.H.
      • Jeha L.
      • Tanner A.
      • Bingaman W.
      • Sperling M.R.
      Late seizures in patients initially seizure free after epilepsy surgery.
      ], long epilepsy duration [
      • Bien C.G.
      • Raabe A.L.
      • Schramm J.
      • Becker A.
      • Urbach H.
      • Elger C.E.
      Trends in presurgical evaluation and surgical treatment of epilepsy at one centre from 1988–2009.
      ,
      • Edelvik A.
      • Rydenhag B.
      • Olsson I.
      • Flink R.
      • Kumlien E.
      • Kallen K.
      • et al.
      Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
      ,
      • Luyken C.
      • Blumcke I.
      • Fimmers R.
      • Urbach H.
      • Elger C.E.
      • Wiestler O.D.
      • et al.
      The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects.
      ,
      • Menon R.
      • Rathore C.
      • Sarma S.P.
      • Radhakrishnan K.
      Feasibility of antiepileptic drug withdrawal following extratemporal resective epilepsy surgery.
      ,
      • Simasathien T.
      • Vadera S.
      • Najm I.
      • Gupta A.
      • Bingaman W.
      • Jehi L.
      Improved outcomes with earlier surgery for intractable frontal lobe epilepsy.
      ,
      • Phi J.H.
      • Kim S.K.
      • Cho B.K.
      • Lee S.Y.
      • Park S.Y.
      • Park S.J.
      • et al.
      Long-term surgical outcomes of temporal lobe epilepsy associated with low-grade brain tumors.
      ], higher age at surgery [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ,
      • Elsharkawy A.E.
      • Behne F.
      • Oppel F.
      • Pannek H.
      • Schulz R.
      • Hoppe M.
      • et al.
      Long-term outcome of extratemporal epilepsy surgery among 154 adult patients.
      ,
      • Schwartz T.H.
      • Jeha L.
      • Tanner A.
      • Bingaman W.
      • Sperling M.R.
      Late seizures in patients initially seizure free after epilepsy surgery.
      ,
      • Fauser S.
      • Essang C.
      • Altenmuller D.M.
      • Staack A.M.
      • Steinhoff B.J.
      • Strobl K.
      • et al.
      Long-term seizure outcome in 211 patients with focal cortical dysplasia.
      ], high baseline seizure frequency [
      • Edelvik A.
      • Rydenhag B.
      • Olsson I.
      • Flink R.
      • Kumlien E.
      • Kallen K.
      • et al.
      Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
      ,
      • Foldvary N.
      • Nashold B.
      • Mascha E.
      • Thompson E.A.
      • Lee N.
      • McNamara J.O.
      • et al.
      Seizure outcome after temporal lobectomy for temporal lobe epilepsy: a Kaplan–Meier survival analysis.
      ], postoperative interictal epileptiform discharges [
      • Rathore C.
      • Panda S.
      • Sarma P.S.
      • Radhakrishnan K.
      How safe is it to withdraw antiepileptic drugs following successful surgery for mesial temporal lobe epilepsy?.
      ,
      • Menon R.
      • Rathore C.
      • Sarma S.P.
      • Radhakrishnan K.
      Feasibility of antiepileptic drug withdrawal following extratemporal resective epilepsy surgery.
      ,
      • Di Gennaro G.
      • Casciato S.
      • D’Aniello A.
      • De Risi M.
      • Quarato P.P.
      • Mascia A.
      • et al.
      Serial postoperative awake and sleep EEG and long-term seizure outcome after anterior temporal lobectomy for hippocampal sclerosis.
      ] and early postoperative seizures [
      • Jeha L.E.
      • Najm I.
      • Bingaman W.
      • Dinner D.
      • Widdess-Walsh P.
      • Luders H.
      Surgical outcome and prognostic factors of frontal lobe epilepsy surgery.
      ,
      • McIntosh A.M.
      • Averill C.A.
      • Kalnins R.M.
      • Mitchell L.A.
      • Fabinyi G.C.
      • Jackson G.D.
      • et al.
      Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery.
      ,
      • Ramesha K.N.
      • Mooney T.
      • Sarma P.S.
      • Radhakrishnan K.
      Long-term seizure outcome and its predictors in patients with recurrent seizures during the first year aftertemporal lobe resective epilepsy surgery.
      ].
      The one predictive factor that is tractable – epilepsy duration before undertaking presurgical investigation – has repeatedly been shown not to have shortened significantly over the years [
      • Engel Jr., J.
      • McDermott M.P.
      • Wiebe S.
      • Langfitt J.T.
      • Stern J.M.
      • Dewar S.
      • et al.
      Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial.
      ,
      • Bien C.G.
      • Raabe A.L.
      • Schramm J.
      • Becker A.
      • Urbach H.
      • Elger C.E.
      Trends in presurgical evaluation and surgical treatment of epilepsy at one centre from 1988–2009.
      ,
      • Rydenhag B.
      • Flink R.
      • Malmgren K.
      Surgical outcomes in patients with epileptogenic tumours and cavernomas in Sweden: good seizure control but late referrals.
      ]. These results from long-term outcome studies underline the importance of earlier identification of good candidates for resective epilepsy surgery. The duration of epilepsy in adults referred for presurgical evaluation is still 15–20 years [
      • Ryvlin P.
      • Cross J.H.
      • Rheims S.
      Epilepsy surgery in children and adults.
      ], a time period which for many of the young adults referred is more than half of their lives. Earlier epilepsy surgery has the important potential to decrease or even prevent many of the disabling psychological and social consequences of epilepsy.

      6. Patterns of remission and relapse

      Several studies have pointed out the changing pattern of seizure control over time which complicates the process of evaluating surgical outcomes. In a retrospective study of 175 patients who had been seizure-free for one year after resective epilepsy surgery, 63% never relapsed during a mean follow-up of 8.3 years. The likelihood of remaining seizure-free declined to 56% over 10 years, but half of the patients who relapsed had at most one seizure per year [
      • Yoon H.H.
      • Kwon H.L.
      • Mattson R.H.
      • Spencer D.D.
      • Spencer S.S.
      Long-term seizure outcome in patients initially seizure-free after resective epilepsy surgery.
      ].
      In a US multi-center follow-up of 223 patients who at some point during follow-up (two to seven years) had entered a two-year remission, 25% relapsed later. Patients who entered a two year remission immediately after surgery were less likely to relapse later than those who had a two-year remission at a later time [
      • Spencer S.S.
      • Berg A.T.
      • Vickrey B.G.
      • Sperling M.R.
      • Bazil C.W.
      • Shinnar S.
      • et al.
      Predicting long-term seizure outcome after resective epilepsy surgery: the multicenter study.
      ]. In another study of 285 patients who had one year of postoperative seizure freedom, 18% had relapsed by five years and 33% by 10 years, but at last follow-up (after a mean of 8 years), only 13% were not seizure free [
      • Schwartz T.H.
      • Jeha L.
      • Tanner A.
      • Bingaman W.
      • Sperling M.R.
      Late seizures in patients initially seizure free after epilepsy surgery.
      ].
      In a recent long-term follow-up from UK of 615 adults, 68–73% of patients had been seizure free (or had only aura) the previous year at any time during follow-up. Patients who were seizure free two years after surgery, had an 80% chance of still being seizure free after another five years, and those who were continuously seizure free five years postoperatively had an 89% chance of still being seizure free after another five years [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ].

      7. Long-term outcomes of antiepileptic drug treatment

      There is no consensus regarding management of antiepileptic drugs (AEDs) after successful epilepsy surgery [
      • Jehi L.
      Medication management after epilepsy surgery: opinions versus facts.
      ] and no systematic studies of the optimal timing of postoperative drug withdrawal in adults. Side effects of AEDs contribute to poor quality of life [
      • Luoni C.
      • Bisulli F.
      • Canevini M.P.
      • De Sarro G.
      • Fattore C.
      • Galimberti C.A.
      • et al.
      Determinants of health-related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments.
      ], and many patients have expectations to withdraw AEDs after successful surgery [
      • Taylor D.C.
      • McMacKin D.
      • Staunton H.
      • Delanty N.
      • Phillips J.
      Patients’ aims for epilepsy surgery: desires beyond seizure freedom.
      ,
      • Hrazdil C.
      • Roberts J.I.
      • Wiebe S.
      • Sauro K.
      • Vautour M.
      • Hanson A.
      • et al.
      Patient perceptions and barriers to epilepsy surgery: evaluation in a large health region.
      ,
      • Ozanne A.
      • Graneheim U.H.
      • Ekstedt G.
      • Malmgren K.
      Patients’ expectations and experiences of epilepsy surgery—a population-based long-term qualitative study.
      ]. On the other hand, patients have many aspects to consider when deciding for or against AED discontinuation, not least the psychosocial consequences of a seizure recurrence with regard to occupational abilities or driving. The framing of risk information influences patients’ decisions [
      • McNeil B.J.
      • Pauker S.G.
      • Sox Jr., H.C.
      • Tversky A.
      On the elicitation of preferences for alternative therapies.
      ] and in one study where medically treated seizure-free patients were counseled about individualized recurrence risks based on a computer-based predictive model, the majority decided to continue AEDs [
      • Jacoby A.
      • Baker G.
      • Chadwick D.
      • Johnson A.
      The impact of counselling with a practical statistical model on patients’ decision-making about treatment for epilepsy: findings from a pilot study.
      ]. Framing of information may be one reason behind the varying proportions of adults seizure-free after epilepsy surgery in whom AEDs have been withdrawn in different studies. In a meta-analysis from 2007 nine studies were identified and a pooled analysis showed that only 19% of seizure-free adults had discontinued AEDs at a mean follow-up of seven years [
      • Tellez-Zenteno J.F.
      • Dhar R.
      • Hernandez-Ronquillo L.
      • Wiebe S.
      Long-term outcomes in epilepsy surgery: antiepileptic drugs, mortality, cognitive and psychosocial aspects.
      ]. One study from UK found that at last follow-up (median 8 years) 28% of seizure-free patients were off AEDs [
      • de Tisi J.
      • Bell G.S.
      • Peacock J.L.
      • McEvoy A.W.
      • Harkness W.F.
      • Sander J.W.
      • et al.
      The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study.
      ] and in a recent US study with a mean follow-up of 4.6 years, 19% of all TLR adults had discontinued AEDs [
      • Yardi R.
      • Irwin A.
      • Kayyali H.
      • Gupta A.
      • Nair D.
      • Gonzalez-Martinez J.
      • et al.
      Reducing versus stopping antiepileptic medications after temporal lobe surgery.
      ]. On the other hand, in an Indian study AED withdrawal was systematically planned for all seizure-free patients after TLR and was successful in 63% of 258 patients who were followed for at least five years [
      • Rathore C.
      • Panda S.
      • Sarma P.S.
      • Radhakrishnan K.
      How safe is it to withdraw antiepileptic drugs following successful surgery for mesial temporal lobe epilepsy?.
      ]. The same center also studied AED withdrawal after extratemporal surgery and found higher seizure recurrence rates than after TLR, with a cumulative probability chance of 52% to be seizure-free and AED free after 10 years [
      • Menon R.
      • Rathore C.
      • Sarma S.P.
      • Radhakrishnan K.
      Feasibility of antiepileptic drug withdrawal following extratemporal resective epilepsy surgery.
      ].
      In a recent meta-analysis of the management of antiepileptic drugs following epilepsy surgery, original studies comparing seizure outcomes in patients who did or did not discontinue AEDs after epilepsy surgery were reviewed [
      • Ladino L.D.
      • Hernandez-Ronquillo L.
      • Tellez-Zenteno J.F.
      Management of antiepileptic drugs following epilepsy surgery: a meta-analysis.
      ]. Sixteen articles fulfilled eligibility criteria and described outcomes in 1456 patients in whom AEDs were discontinued and 685 patients with no discontinuation. The timing of withdrawal was reported to be mainly influenced by patient preference, a specific protocol for AED reduction was used in a minority of studies. The average interval to start AED reduction was 14 months and to complete AED discontinuation 30 months. The mean postoperative follow-up of all studies was 5.4 years (range 1–12 years). Interestingly, the authors found that the postoperative risk of relapse was lower in patients who withdrew AEDs than in those who stayed on drugs (OR 0.39, 95% CI 0.30–0.51), and suggest that most likely this difference is related with a selected population where discontinuation was attempted, who had a low risk profile for seizure recurrence. Another recent meta-analysis reviewed seizure recurrence in both medically and surgically treated patients and found no significant difference of long-term cumulative recurrence risk between surgical and medication-only populations [
      • Lamberink H.J.
      • Otte W.M.
      • Geleijns K.
      • Braun K.P.
      Antiepileptic drug withdrawal in medically and surgically treated patients: a meta-analysis of seizure recurrence and systematic review of its predictors.
      ]. The cumulative relapse rates after start of postoperative AED reduction were 14% at 1 year, 21% at 2, and 29% after five or more years. No consistent set of predictors could be identified because a large number of variables were identified, many studies reported contradicting results, study populations varied considerably, and the quality of the original studies was often low. The risk of permanent loss of seizure control following postoperative AED withdrawal has been shown to be low: 75% (95% CI 72.4–79%) of patients who relapse regain seizure freedom after restart of medication [
      • Ladino L.D.
      • Hernandez-Ronquillo L.
      • Tellez-Zenteno J.F.
      Management of antiepileptic drugs following epilepsy surgery: a meta-analysis.
      ].
      In a prospective longitudinal population based Swedish long-term follow-up study the proportion of patients who had discontinued AED treatment increased over time from 2, 5 to the 10-year follow-up at which time-point 43% of the seizure-free adults had stopped AED treatment [
      • Edelvik A.
      • Rydenhag B.
      • Olsson I.
      • Flink R.
      • Kumlien E.
      • Kallen K.
      • et al.
      Long-term outcomes of epilepsy surgery in Sweden: a national prospective and longitudinal study.
      ]. Since there is no common Swedish protocol for discontinuation of AEDs in seizure-free patients, this trend could be interpreted to reflect that patients and their physicians trust the seizure-free state more as time goes by.

      8. Long-term employment outcomes

      Knowledge about employment outcomes after epilepsy surgery is of considerable importance, both from a health economic perspective and in relation to quality of life [
      • Perry M.S.
      • Duchowny M.
      Surgical versus medical treatment for refractory epilepsy: outcomes beyond seizure control.
      ,
      • Chin S.
      • Berg A.T.
      • Spencer S.S.
      • Sperling M.R.
      • Haut S.R.
      • Langfitt J.T.
      • et al.
      Employment outcomes following resective epilepsy surgery.
      ]. However, long-term studies on employment outcomes after resective epilepsy surgery are scarce. Most are retrospective and cross-sectional and focus only on patients who have had temporal lobe resections [
      • Wilson S.J.
      • Coleman H.
      Long-term educational and vocational outcomes of adults after epilepsy surgery.
      ]. There are some methodological aspects to consider when evaluating studies on employment outcome. Especially for people who are unemployed before surgery, it can take more than two years following surgery to find employment [
      • Sperling M.R.
      • Saykin A.J.
      • Roberts F.D.
      • French J.A.
      • O’Connor M.J.
      Occupational outcome after temporal lobectomy for refractory epilepsy.
      ]. Studies with cross-sectional design reporting an average follow-up of 5 years may well combine the employment outcomes of patients from 6 months to 10 years post-surgery and hence not take this time perspective into account. Also, studies may include patients ranging in age from 17 to 60 years at the time of surgery, with widely differing employment perspectives, and report on them collectively at group level. Cross-sectional studies are also more sensitive to the current state of the labor market, and people with health problems may have more difficulties to find or retain work in times of recession [
      • Wasade V.S.
      • Elisevich K.
      • Tahir R.
      • Smith B.
      • Schultz L.
      • Schwalb J.
      • et al.
      Long-term seizure and psychosocial outcomes after resective surgery for intractable epilepsy.
      ].
      Hence, it is not surprising that results from longer-term vocational outcome studies after epilepsy surgery are inconsistent. Some investigators found no change in the number of employed patients after surgery [
      • Lazow S.P.
      • Thadani V.M.
      • Gilbert K.L.
      • Morse R.P.
      • Bujarski K.A.
      • Kulandaivel K.
      • et al.
      Outcome of frontal lobe epilepsy surgery.
      ,
      • Chin S.
      • Berg A.T.
      • Spencer S.S.
      • Sperling M.R.
      • Haut S.R.
      • Langfitt J.T.
      • et al.
      Employment outcomes following resective epilepsy surgery.
      ,
      • Augustine E.A.
      • Novelly R.A.
      • Mattson R.H.
      • Glaser G.H.
      • Williamson P.D.
      • Spencer D.D.
      • et al.
      Occupational adjustment following neurosurgical treatment of epilepsy.
      ,
      • Wass C.T.
      • Rajala M.M.
      • Hughes J.M.
      • Sharbrough F.W.
      • Offord K.P.
      • Rademacher D.M.
      • et al.
      Long-term follow-up of patients treated surgically for medically intractable epilepsy: results in 291 patients treated at Mayo Clinic Rochester between July 1972 and March 1985.
      ,
      • Reeves A.L.
      • So E.L.
      • Evans R.W.
      • Cascino G.D.
      • Sharbrough F.W.
      • O’Brien P.C.
      • et al.
      Factors associated with work outcome after anterior temporal lobectomy for intractable epilepsy.
      ], others found a decrease in employment for patients with continuing seizures, but no change for seizure-free patients [
      • Asztely F.
      • Ekstedt G.
      • Rydenhag B.
      • Malmgren K.
      Long term follow-up of the first 70 operated adults in the Goteborg Epilepsy Surgery Series with respect to seizures, psychosocial outcome and use of antiepileptic drugs.
      ], while some reported increased employment [
      • Sperling M.R.
      • Saykin A.J.
      • Roberts F.D.
      • French J.A.
      • O’Connor M.J.
      Occupational outcome after temporal lobectomy for refractory epilepsy.
      ,
      • Jones J.E.
      • Berven N.L.
      • Ramirez L.
      • Woodard A.
      • Hermann B.P.
      Long-term psychosocial outcomes of anterior temporal lobectomy.
      ,
      • George L.
      • Iyer R.S.
      • James R.
      • Sankara Sarma P.
      • Radhakrishnan K.
      Employment outcome and satisfaction after anterior temporal lobectomy for refractory epilepsy: a developing country’s perspective.
      ,
      • Zarroli K.
      • Tracy J.I.
      • Nei M.
      • Sharan A.
      • Sperling M.R.
      Employment after anterior temporal lobectomy.
      ]. A large prospective US multicenter study found little change in the whole cohort, but interestingly 25% of seizure-free patients who previously were disabled or unemployed were in gainful employment two years after surgery [
      • Chin S.
      • Berg A.T.
      • Spencer S.S.
      • Sperling M.R.
      • Haut S.R.
      • Langfitt J.T.
      • et al.
      Employment outcomes following resective epilepsy surgery.
      ].
      In a recent prospective population based Swedish long-term follow-up study of employment at long term (5, 10 and 15 years) after resective epilepsy surgery there were no net employment gains in the whole cohort of operated patients [
      • Edelvik A.
      • Flink R.
      • Malmgren K.
      Prospective and longitudinal long-term employment outcomes after resective epilepsy surgery.
      ]. However, subgroups based on preoperative employment status and postoperative seizure outcome had different pathways for long-term employment. In the multivariate analysis, the strongest predictors of being employed postoperatively at any time point were having employment preoperatively, favorable seizure outcome and younger age at surgery. Odds ratios for being employed 10 years after surgery were 6.5 (95% CI 3.0–14.1) for full-time employment preoperatively, 2.6 (95% CI 1.1–6.3) for part-time employment preoperatively, 2.5 (95% CI 1.4–4.8) for seizure freedom and 0.6 (95% CI 0.4–0.8) for younger age at surgery, calculated per 10 years younger. On the other hand, 16% of the patients who were on benefits before surgery and became seizure free worked full-time after 2 years, increasing to around 30% after 5 and 10 years.
      In this study data on full-time employment were also compared between the general Swedish population and seizure-free patients (cf Fig. 2). In the general population, 65–71% of those between 25 and 54 worked full-time, decreasing to 53% for people aged 55–64. This can be compared to the seizure-free patients with 5 and 10 year follow-up after surgery, where 36–65% worked full-time up to age 54, but only 24–27% of the patients worked full-time after the age of 55. The reasons for this need to be further investigated. One possibility is that having had epilepsy for half of a person’s life leads to impairments that may not always be measurable and that these may become more apparent with age [
      • Wilson S.J.
      • Coleman H.
      Long-term educational and vocational outcomes of adults after epilepsy surgery.
      ].
      Fig. 2
      Fig. 2Full-time employment for seizure free patients and in the general population.
      (Reprinted with permission from Wolters Kluwer Health, Inc., Neurology, Edelvik et al. [
      • Edelvik A.
      • Flink R.
      • Malmgren K.
      Prospective and longitudinal long-term employment outcomes after resective epilepsy surgery.
      ], Fig. 2)
      Percentage with full-time employment (>35 h/week) in the general Swedish population (black bars) between 2005 and 2010, and in seizure-free patients (blue bars) at follow-ups 2, 5, 10 and 15 years after surgery. Data are shown for different age groups (decades). Numbers above bars represent no. of patients in each group. Abbreviation: Gen pop = general population.
      Longitudinal studies are needed, making it possible to track individual trajectories of employment outcomes, relative to non-surgically treated epilepsy controls and also taking the employment in the general population into consideration. Other factors of probable importance for retaining or obtaining work, such as cognitive level and psychiatric or other comorbidities also need to be addressed.
      The effectiveness of postoperative vocational rehabilitation strategies is another important aspect which requires systematic research. The literature is surprisingly scarce, but the importance of rehabilitation after epilepsy surgery was highlighted in a recent study where taking part in a rehabilitation program had the same impact as seizure freedom on employment outcome [
      • Thorbecke R.
      • May T.W.
      • Koch-Stoecker S.
      • Ebner A.
      • Bien C.G.
      • Specht U.
      Effects of an inpatient rehabilitation program after temporal lobe epilepsy surgery and other factors on employment 2 years after epilepsy surgery.
      ].

      9. Conclusions and future directions

      Epilepsy surgery is an efficacious treatment for selected persons with drug-resistant focal epilepsy, rendering many seizure-free and others significantly improved. For many years follow-up data were limited to a few years after surgery. However, most adult prospective surgical candidates are young, and in order for them to make an informed decision about the treatment option of neurosurgery, it is imperative that the long-term perspective forms an integral part of presurgical counseling.
      Long-term longitudinal observational studies are necessary in order to obtain valid outcome data. From a number of such studies the proportion of patients who have been continuously free from seizures with impairment of consciousness since resective epilepsy surgery is around 40–50% after 10 years while a higher proportion have been seizure-free at least a year at each time-point assessed. Hopefully the advances in neuroimaging, neurophysiological investigations, and development of methods for data postprocessing which have increased the possibility of accurately localizing the epileptogenic zone to be resected, will also lead to even better long-term outcomes.
      In a recent volume on long-term outcomes of epilepsy surgery in adults and children [
      • Malmgren K.
      • Baxendale S.
      • Cross J.H.
      Long-term outcomes of epilepsy surgery in adults and children.
      ], the aim was to address outcomes beyond seizure control and beyond 5 years of follow-up. In summarizing the literature it turned out not only that long-term studies of seizure outcome were relatively rare, but that studies of the wider aspects of surgical outcome were even more scarce. There is an urgent need for more longitudinal observational studies of non-seizure outcomes. Such studies need to consider individual patient trajectories over time and take comorbidities into account.
      Shortening the duration of epilepsy at surgery by referring patients for presurgical investigation earlier is the single most important factor possible to influence that can improve the prognosis for good seizure outcome of epilepsy surgery. Even if earlier evaluation for epilepsy surgery does not per se carry a higher remission rate, earlier evaluation for surgery would also help preventing many of the psychosocial problems related to longstanding drug resistant epilepsy.

      Funding

      The study was funded by grants from the Sahlgrenska Academy at the University of Gothenburg through the LUA/ALF agreement (grant ALFGBG-429901 ).

      Conflict of interest statement

      The authors have no conflicts of interest with regard to the present work. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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