Long-term seizure outcome of surgery versus no surgery for drug-resistant partial epilepsy: A review of controlled studies

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1 CRITICAL REVIEW AND INVITED COMMENTARY Long-term seizure outcome of surgery versus no surgery for drug-resistant partial epilepsy: A review of controlled studies *Dieter Schmidt and yzknut Stavem *Epilepsy Research Group Berlin, Germany; yhøkh, Research Centre, Akershus University Hospital, Lørenskog, Norway; and zfaculty of Medicine, University of Oslo, Oslo, Norway SUMMARY A majority of patients with formerly drug-resistant temporal lobe epilepsy become seizure-free after surgery. However, apart from one 12-month randomized trial, it is unclear how many become seizure-free because of surgery. To determine the net benefit of surgery, we performed a systematic review and meta-analysis of the published evidence of how many patients in similar studies become seizure-free without surgery. Of 155 potentially eligible articles reviewed in full text, 29 (19%) fulfilled eligibility criteria. After excluding 9 publications, 20 studies form the base of evidence. Overall, 719 of 1,621 (44%) of patients with mostly temporal lobe surgery were seizure-free compared to 139 of 1113 (12%) of nonoperated controls [pooled random effects relative risk (RR) 4.26, 95% confidence interval (CI) ]. The pooled risk difference in favor of surgery was 42% (95% CI 32 51%). We found no comparative outcome data in patients with extratemporal lobe epilepsy only. The available evidence from mostly nonrandomized observational studies indicates that in appropriately selected patients with drugresistant temporal lobe epilepsy, the combination of surgery with medical treatment is 4 times as likely as medical treatment alone to achieve freedom from seizures. KEY WORDS: Epilepsy surgery, Long-term outcome, Chronic epilepsy, Antiepileptic drugs, Seizure prognosis. Adjunctive treatment with resective surgery and a change of medical regimen are both standards of care for eligible patients with chronic drug-resistant epilepsy (Engel et al., 2003; French et al., 2004). A meta-analysis of surgical outcome indicates that 2 years after surgery 55% of patients with formerly drug-resistant temporal lobe epilepsy are completely seizure free and 68% are free of complex partial seizures (Chapell et al., 2003). It is unclear, however, how many patients become seizure-free because of surgery. To determine the net-benefit of surgery, one would need to know how many patients in similar studies become seizure-free without surgery (Chapell et al., 2003). However, apart from one 12-month Accepted October 29, 2008; Early View publication February 23, Address correspondence to Prof. Dr. Dieter Schmidt, Epilepsy Research Group, Goethestr.5, D Berlin, Germany. Wiley Periodicals, Inc. ª 2009 International League Against Epilepsy randomized trial, the long-term seizure outcome of surgery versus medical treatment in nonoperated patients is not well known (Wiebe et al., 2001; TØllez-Zenteno et al., 2005). Although most studies have focused on seizure outcome in surgical cases, a number of epilepsy centers have reported clinical observations of seizure outcomes in surgical versus nonoperated patients, including patients who were found unsuitable for surgery (TØllez-Zenteno et al., 2005). The strength of inference that can be derived from these nonrandomized studies is clearly less robust than that from the only randomized trial; however, data from cohort studies still inform about clinical practice in many areas, including epilepsy. Meta-analyses of observational data have a role in medical effectiveness research, provided that the possible sources of heterogeneity between studies and the influence of biases or confounding factors are carefully examined (Egger et al., 1998). Furthermore, the question of long-term outcome may not be amenable to randomized trials because of feasibility and ethical 1301

2 1302 D. Schmidt and K. Stavem issues. In addition, a comparison of surgical outcome versus a change in medical regimen has become clinically important, because recent outcome data in apparently drug-resistant epilepsy, including in nonsurgical candidates, suggest that up to 21% of patients may be rendered seizure-free for more than 2 years by a change in regimen (Selwa et al., 2003). Given that epilepsy is drug-resistant in as many as one in three newly diagnosed patients (Kwan & Brodie, 2000; Schmidt & Lçscher, 2005), uncertainty about the comparative efficacy of surgery versus a change of medical regimen in nonoperated patients, the two commonly used treatments for chronic epilepsy, is a strategic problem. This scenario prompted us to examine the evidence for long-term seizure freedom following surgery and after drug treatment in nonoperated patients. Methods Data sources A medical librarian performed a comprehensive literature search of the PubMed, Medline, Embase, Index Medicus, and Cochrane databases (search strategy in Appendix). Literature searches were restricted to fulllength articles published between January 1947 and June 2007 in English, German, or French. In addition, we also hand-searched bibliographies of reviews, original articles, and book chapters, and consulted experts about other studies. Study selection and classification Two reviewers independently applied the following study inclusion criteria: reports of 20 patients of any age undergoing resective epilepsy surgery utilizing a control group, outcomes reported after a mean/median follow-up of 1 year after surgery or initial evaluation, quantitative report of seizure freedom with or without concurrent antiepileptic drug (AED) treatment, and description of type of surgery and number of patients undergoing each intervention. We further classified studies by surgical topography into those studies reporting outcomes of temporal lobe surgery, and those grouping temporal and extratemporal surgery together. We found a total of 31 publications and excluded 11 articles. The remaining 20 publications form the base of evidence for this review (see results). Data gathering Two reviewers independently abstracted all data, resolving disagreements through discussion. We accepted outcome definition as used by authors in each study. These usually referred to seizure outcome in terms of seizure freedom. Data analysis For comparison of seizure-free outcome between surgical versus nonsurgical groups, we produced summary estimates for the studies, presenting the RR and its 95% CI, with values >1 favoring surgery. We aggregated the RRs in tables and a forest plot. The analysis was stratified different ways according to subgroups as a sensitivity analysis, because of heterogeneity between studies. We had considered assessing the influence of different variables in a meta-regression analysis, but we realized that the limited number of studies, the heterogeneity between the studies, and association between various variables would raise a number of problems that could not be resolved. Therefore, we have abstained from presenting a meta-regression and instead presented RRs for a number of subgroups. Two studies reported more than one followup period (McLachlan et al., 1997; Picot et al., 2008), and one had separate reports for different time intervals (Stavem & Guldvog, 2005; Stavem et al., 2008). For these studies, we assessed each follow-up period separately. Hence, in one comparison, we included studies with several follow-up periods in the same population, presenting results for 24 months and >24 months. In the remaining analyses, we included only results from the longest follow-up time for each study, presenting results according to length of follow-up ( 24 months and >24 months), publications with and without zero seizure-free outcome in the medical control group, year of publication ( and ), surgical topography: temporal lobe versus temporal lobe plus extratemporal lobe, and study design. Because of lack of information, we could not perform a subgroup analysis for duration of treatment prior to surgery; definition of seizure-freedom; age at surgery; etiology, mesial temporal sclerosis versus other etiology; and choice of nonoperated group, patients on waiting lists for surgery versus those found ineligible for surgery. We also summarized the RRs of being without AEDs after surgery compared to no surgery at the longest follow-up in the studies (n = 4) that reported this, using a similar meta-analytic technique. The meta-analyses were done using random effects models, aggregating studies with a weighting equal to the inverse of the variance of the estimate for the study. Random effects models were chosen because of heterogeneity between studies, although fixed effects models would have yielded essentially similar results. The weights are not shown on the forest plots or in the tables. We assessed interstudy variability (heterogeneity) by describing I 2, that is, the percentage of total variation across studies that is caused by heterogeneity rather than chance (Higgins et al., 2003). A percentage of 25%, 50%, and 75% has been suggested to indicate low, medium, and high heterogeneity (Higgins et al., 2003). In addition we present the results of a test for heterogeneity using DerSimonian and Laird s Q (DerSimonian & Laird, 1986). Because of heterogeneity between studies, we present results for subgroups rather than for the aggregate of all studies. For seizure outcome analysis of surgery and medical treatment, we

3 1303 Epilepsy Surgery versus No Surgery used seizure-free versus not seizure-free, based on the classifications used in the included papers. The authors of the papers used Engel s outcome classification (Engel et al., 2003), modifications of this, or their own outcome classifications. The overall results are also presented using a similar metaanalysis with risk differences as outcome. We used the Metan procedure in Stata version 10 for all analyses (Stata Corp., College Station, TX, U.S.A.). Results Evidence base The literature search yielded 155 references, of which 31 (20%) were potentially eligible and were reviewed independently by two reviewers. Twenty (13%) fulfilled the eligibility criteria and constitute this analysis data set (Fig. 1). Figure 1. Search strategy and evidence base. *Reasons for exclusion were: duplicate publications, that is, studies sharing the same or overlapping patient populations at a similar follow-up period (Bien et al., 2001; Helmstaedter et al., 2003, overlapping with Bien et al., 2006; Haglung & Moretti Ojemann, 1993, overlapping with Moretti Ojemann & Jung, 2006; Guldvog et al., 1994; Stavem & Guldvog, 2005, overlapping with Stavem et al., 2008; Mikati et al., 2004; had overlapping populations with Mikati et al., 2006; Picot et al., 2004 had overlapping populations with Picot et al., 2008; no quantitative seizure outcome data for the nonoperated group F: Rausch & Crandall, 1982; Baxendale & Thompson, 1996; Kellett et al., 1997; follow-up of less than 1 year E: (Aydemir et al., 2004). Epilepsia ILAE Study population and trial design We identified 20 controlled studies (Table 1). Except for one (Wiebe et al., 2001), all studies were nonrandomized (Table 1). Two studies reported more than one follow-up period (McLachlan et al., 1997; Picot et al., 2008), and one had separate reports for different time intervals (Stavem & Guldvog, 2005; Stavem et al., 2008). The outcome of temporal lobe surgery only was assessed in 17 of 20 studies, the other three studies reported combined outcome of temporal and extratemporal lobe epilepsy (Table 1). We found no studies on seizure outcome for extratemporal lobe surgery only versus AED treatment without surgery. In 16 of the 20 studies, controls were patients evaluated for surgery but who did not undergo resective surgery, three studies did not describe surgical eligibility of their control group, and in one study patients were randomized as controls before surgical eligibility was assessed (Table 2). Participants in the medical control group who were evaluated for surgery either failed to meet criteria for surgery, declined surgery, or were waiting for surgery and continued to receive AED treatment (Table 2). In three early studies, controls were patients treated with AEDs undergoing craniotomy without excision of brain tissue (Penfield & Steelman, 1947; Penfield & Paine, 1955; Ommaya, 1963). Definitions of seizure-freedom in the surgical studies fell into four main categories. In most studies (8 of 20 studies, 40%) the measure for seizure freedom was undefined. In 5 of 20 studies (25%), Engel s classification was used (Engel et al., 1993), 1 study used in addition the ILAE classification (Wieser et al., 2001); in 3 of 20 studies, patients were free of any seizures and auras, whereas in a further four studies, patients having auras were considered to be seizure-free (Table 1). The definition of seizure-freedom for surgical and nonsurgical treatment outcome is given in Table 1. Ninety percent of the studies focused on seizure freedom at the last follow-up or the last year, 5% did not specify a time frame, and 5% offered no definition. In 90% of the studies, seizure-free outcome was determined after the first surgery; in two studies 5% of patients in each study underwent a second surgical procedure (Vickrey et al., 1995; Bien et al., 2006). In 20% of studies, a change in AEDs was reported after surgery (Penfield & Steelman, 1947; Vickrey et al., 1995; Wiebe et al., 2001; Yasuda et al., 2006). Although the total number of AEDs was lower in the surgical group, a dose increase of AEDs was reported in two studies (Wiebe et al., 2001; Yasuda et al., 2006). In one study, surgically treated patients who became seizure-free after surgery after a change of medical regimen, including a modern AED, were excluded (Kumlien et al., 2002).

4 1304 D. Schmidt and K. Stavem Table 1. Study population and trial design in 20 controlled studies comparing seizure-free outcome in operated patients and nonoperated controls. The number of surgical patients and controls is given in Figure 2 Authors (year) Study design Seizure-free outcome measures (surgical) Type of surgery Follow-up (years) Seizure-free outcome measures (nonsurgical) Seizure-free (nonsurgical) McLachlan et al. (1997) C/CR No auras TL 1, 2 Undefined No Gilliam et al. (1999) C/CR No auras, with auras TL 2 No auras, with auras No O Donoghue et al. (1998) C/CR Undefined TL 2 Undefined Yes Altshuler et al. (1999) C With auras TL 4 13 With auras Yes Ommaya (1963) C/CR No aura TL 4 13 No auras No Penfield and Steelman (1947) C Undefined TL 4 13 Undefined No Penfield and Paine (1955) C/CR Undefined TL 4 13 Undefined No Vickrey et al. (1995) C/CR No auras, with auras TL + XTL 4 13 No auras, with auras Yes Markand et al. (2000) C Engel class I, no auras TL 1 No auras No Wiebe et al. (2001) RCT No auras, with auras TL 1 No auras, with auras Yes Yasuda et al. (2006) a C Engel class IA TL 1 Engel class IA Yes Mikati et al. (2006) C Engel class IA TL 2 Engel class IA Yes Bien et al. (2006) C/CR Undefined TL 4 13 Undefined Yes Derry et al. (2001) C Undefined TL 4 13 Undefined Yes Jones et al. (2002) C No auras TL 4 13 No auras Yes Kumlien et al. (2002) C Undefined TL 4 13 Undefined Yes Li (2002) C/CR Undefined TL 4 13 Undefined No Moretti Ojemann and Jung (2006) C Author specific TL 4 13 with auras Yes Stavem et al. (2008) C/CR Undefined TL + XTL 4 13 Undefined Yes Picot et al. (2008) C Engel I, ILAE TL + XTL 1, 2, 4 13 Engel I, ILAE Yes a Additional data supplied by study author on request. C, cohort; CR, cross-sectional; ILAE, ILAE, International League Against Epilepsy; RCT, randomized controlled trial; TL, outcome for temporal lobe surgery only; TL + XTL, combined outcome after temporal and extratemporal lobe surgery. Seizure-free outcome in studies comparing surgical versus drug treatment The weighted pooled proportion of long-term seizure-free patients was determined in a total of 20 studies comparing surgical versus medical outcome (Fig. 2). Overall, 719 of 1,621 patients (44%) with mostly temporal lobe surgery were seizure free compared to 139 of 1,113 (12%) of nonoperated controls (RR 4.26, 95% CI ). The risk difference between surgery and medical treatment without surgery was 42% (95% CI 32 51%) in favor of surgery. Assessment of heterogeneity by the I 2 method showed moderate heterogeneity of 60% (Fig. 2), and Q was (p < 0.001). In four studies that reported how many patients were off AEDs at the end of follow-up, more patients were off AEDs in the surgical group versus the nonsurgical group; 32% vs. 6%, with an estimated pooled RR for being off AEDs with surgery of 4.67 (95% CI ) compared to medical treatment only (McLachlan et al., 1997; Altshuler et al., 1999; Derry et al., 2001; Stavem et al., 2008). Here, heterogeneity between studies was low with I 2 of 0% and Q of 0.40 (p = 0.94). Factors that may influence seizure-free outcome In a sensitivity analysis, we explored the impact of potential explanatory factors for seizure-free outcome of surgical versus medical studies in the study design and the study population (Table 3). The heterogeneity could also be reduced in some of the subgroups. For assessment of outcome in different study designs we included: duration of follow-up, random controlled trial (RCT) versus cohort or cohort/cross-sectional, and the effect of excluding seven medical studies with zero seizure-free outcome (Table 3). For assessment of outcome in a different study population we included: temporal lobe surgery versus studies reporting a grouped outcome of temporal plus extratemporal lobe surgery, studies of surgery published before 1999 (Table 3). In all subgroups surgery had a statistically better outcome than continued medical treatment. None of the examined factors seemed to have a great influence of the seizure-free outcome of surgical versus no surgical treatment (Table 3). We did not find sufficient data to explore other potential factors such as age, reasons for patients not to have surgery, specific etiologies, or different definitions of seizure-free outcome.

5 1305 Epilepsy Surgery versus No Surgery Table 2. Description of medical controls in the included studies. Participants in the medical control group who were evaluated for surgery either failed to meet criteria for surgery (U), declined surgery (R), or were waiting for surgery (W) and continued to receive antiepileptic drug (AED) treatment. In three early studies, controls were patients undergoing craniotomy without excision of brain tissue (S), and in three studies surgical eligibility of controls was not described (N). The number of control patients for each study is given in Figure 2 Authors (year) Description of controls McLachlan et al. (1997) Patients evaluated for surgery, but not operated on for various reasons (R, U) Gilliam et al. (1999) Patients on waiting list after being evaluated and selected for surgery with anterior temporal lobectomy in 1995 and 1996 (W) O Donoghue et al. (1998) Patients with definite epilepsy seen consecutively in an epilepsy clinic with a follow-up of 1 year. A total of 374 patients from 183 consecutive with definite epilepsy at an epilepsy follow-up clinic with 1 year follow-up, and 191 consecutive patients referred for video-eeg telemetry for assessment of epilepsy surgery (excl. those with IQ < 70). Surgical ineligibility of controls was not described (N) Altshuler et al. (1999) Patients undergoing presurgical evaluation, who did not have surgery for lack of localized seizure focus (12 of 13) or extratemporal focus not suitable for anterior temporal lobe resection (1 of 13) (U) Ommaya (1963) Patients with a diagnosis of temporal lobe epilepsy presenting for surgery, were evaluated and underwent craniotomy, but no removal of brain tissue because of lacking focal activity (U, S) Penfield and Steelman (1947) Patients operated on with craniotomy and cortical excision treatment group (n = 59) versus craniotomy without cortical excision (controls) (n = 16) (U, S) Penfield and Paine (1955) Patients with negative explorations operated on between 1945 and 1950, versus surgery patients (U, S) Vickrey et al. (1995) Patients were evaluated for surgery, but not operated on; no identified focus in 42 (91%), two contraindications for surgery, two withdrew from surgery or evaluation (R, U) Markand et al. (2000) Patients evaluated for surgery who were considered unsuitable for anterior temporal lobe resections or elected against surgery (R, U) Wiebe et al. (2001) Patients were randomized to a delay of presurgical evaluation for 1 year or surgery (W) Yasuda et al. (2006) a Medically treated patients with mesial temporal lobe epilepsy followed for more than 12 months (personal communication by the study author), waiting for finishing presurgical evaluation, waiting for surgery after evaluation, or those unsuitable for surgery versus patients undergoing temporal lobe surgery (W, U) Mikati et al. (2006) Individually matched patients undergoing presurgical evaluation, who were not eligible for surgery (no single seizure focus, or unacceptable neurologic risk) versus consecutive patients undergoing surgery (75% temporal lobe resections) (U) Bien et al. (2006) Patients not eligible for surgery after presurgical assessment (focus not identified, multiple foci, unacceptable neurologic risk) versus surgical patients (W, U) Derry et al. (2001) Evaluated but ineligible patients receiving medical management followed for 8.5 years versus surgical patients (U) Jones et al. (2002) Individuals who were evaluated for surgery but did not proceed to surgery and were receiving AED treatment versus surgical patients (U) Kumlien et al. (2002) Medically treated patients with MRI-verified mesial temporal sclerosis (excluding dual pathology, nonepileptic seizures, nonadherence, uncertain EEG findings) who were considered unsuitable for surgery (no reasons given) versus surgical patients (U) Li (2002) Patients evaluated as surgical candidates who declined surgery or were found otherwise unsuitable for surgery versus surgical patients (U) Moretti Ojemann and Controls were patients with refractory epilepsy who were given medical treatment. Surgical ineligibility of Jung (2006) controls not described (N) Stavem et al. (2008) Patients operated on between 1948 and 1992 with individually matched nonoperated controls hospitalized for severe epilepsy. Matched for age, sex, and seizure type. Surgical ineligibility of controls not described (N) Picot et al. (2008) Controls were patients with refractory epilepsy who were given medical treatment. Following presurgical exploration, 44% of controls were ineligible for surgery (U) a Additional data supplied by study author on request. Discussion The three main results of our review of seizure-free outcome in a total of 2,734 patients with drug-resistant epilepsy after temporal lobe surgery versus medical treatment in broadly similar nonoperated patients are first, that on average, 719 of 1,621 (44%) of patients with mostly temporal lobe surgery were seizure free compared to 139 of 1,113 (12%) of nonoperated controls (pooled RR 4.26, 95% CI ), or a pooled risk difference of 42% (95% CI 32 51%), underscoring that the combination of surgery with medical treatment is more efficacious than medical treatment alone, confirming the result of the only randomized study in the literature (Wiebe et al., 2001). In addition, in the small number of studies reporting AEDfree outcome, more than four times more surgical patients were able to discontinue AEDs compared to nonsurgical controls RR 4.67 (95% CI ). Second,

6 1306 D. Schmidt and K. Stavem Figure 2. Forest plot of the proportion of patients who are seizure-free after surgical treatment and of nonoperated controls. Event = seizure-free patients. Seizure freedom is shown as defined by study authors. AEDs may have been discontinued in either group. The black marker and the horizontal lines show the relative risk (RR) and 95% confidence interval (CI) for each trial. The size of the shaded square is proportional to the weight of the study (% weight) in the pooled estimated RR. The diamond represents the pooled RR and 95% CI, using a random effects model. I 2 is a measure of heterogeneity between the studies (see Methods). Epilepsia ILAE nevertheless, it is remarkable that seizure-free outcome was observed in 12% of similar patients without surgery by AED treatment alone. This shows that drug resistance can be overcome by medical treatment in a minority of patients after having experienced lack of seizure control for many years. Third, no evidence is available for seizurefree outcome of extratemporal surgery versus no surgery. The surgical outcome studies that were included in our analysis (n = 20) had median 56% (range 7 85%) seizure-free patients by authors definition, which is similar to the outcome of the only randomized trial where it was reported that among the 40 surgery patients 38% were completely free of seizures and 58% were free of seizures impairing awareness (Wiebe et al., 2001). We found two reviews in the literature covering a small number of studies on seizure outcome of surgical versus medical treatment (Cucherat, 2004; Tellez-Zenteno et al., 2007). In one review covering five studies, improvement was noted in surgical patients compared with controls without providing quantitative outcome data (Tellez-Zenteno et al., 2007). An earlier review by Cucherat (2004) covered four studies, including three studies reviewed by Tellez-Zenteno et al. (2007) and the only randomized controlled trial by Wiebe et al. (2001). Cucherat (2004) concluded that the evidence was very limited, except for the trial of Wiebe et al. (2001). The long-term seizure-free outcome of nonsurgical patients with chronic drugresistant epilepsy in our review of median 5% (range 0 35%) of the studies (n = 20) is similar to that observed for older AEDs in nonsurgical patients in other series, which, however, provided no data for surgical patients (14%, Bauer & Burr, 2001; 0%, Huttenlocher & Hapke,

7 1307 Epilepsy Surgery versus No Surgery Table 3. Sensitivity analyses with different cross-classifications of studies, showing pooled relative risks (RRs) of seizure-freedom of surgery versus medical treatment without surgery according to individual study features. The RRs, which were determined from random effect models are similar and their 95% confidence intervals (CIs), are overlapping. The table also shows the number of events (=seizure-free patients) and an index of heterogeneity (see footnote) Study feature No. of studies Relative risk (95% CI) Events treatment Events control I 2,% d p-value e Follow-up duration, all papers, longest follow-up of each study a 24 months or less (2.73, 17.46) 233/421 74/ <0.001 More than 24 months (2.67, 5.47) 486/ / Seizure-free controls only b, and longest follow-up (2.65, 4.63) 494/ / of each study b 24 months or less (2.11, 5.63) 103/203 74/ More than 24 months (2.48, 5,22) 391/752 65/ Follow-up, seizure-free controls only, all papers, allowing for more than one follow-up period for each paper c 24 months or less (2.76, 6.06) 250/ / More than 24 months (2.48, 5.22) 391/752 65/ Year of publication, longest follow-up of each study a (2.14, 10.38) 332/966 69/ (2.89, 6.67) 387/655 70/ Surgical topography, longest follow-up of each study a Temporal lobe (3.05, 7.46) 561/ / <0.001 Temporal and extratemporal lobe combined (2.31, 6.30) 158/353 32/ Study design, longest follow-up of each study a Cohort/randomized controlled trial (3.05, 7.32) 320/540 49/ Cohort/cross-section (2.16, 6.37) 399/ / a Only including the longest follow-up period reported in each study population. b Excluding studies with no seizure-free patients in the control group. c Two papers presented results for more than one follow-up period. d Proportion of the total variance due to between study variance (I 2, see Methods). e Der Simonian and Laird Q statistic (see Methods). 1990; 10%, Harbord & Manson, 1987). More recently, it was shown that a significant minority of patients (16.6%) were rendered seizure-free by addition of newly administered AEDs, even after failure of two to five past antiepileptic drugs (Schiller & Najjar, 2008). In a clinical observation of 155 nonsurgical adult patients with chronic epilepsy that had been resistant to previous drug therapy, 16% of all drug introductions resulted in seizure freedom (defined as seizure freedom at last follow-up for 12 months or longer), and 28% of the patients were rendered seizure free by a drug introduction (Luciano & Shorvon, 2007). Although our large review summarizes the available literature on seizure-free outcome in a total of more than 2,700 patients with drug-resistant epilepsy undergoing surgery versus no surgery, it has a number of limitations. One of the important limitations of most studies in our review is the lack of randomization and the inherent bias in the selection of control groups, which because of the nature of the surgery may not be entirely comparable to the surgical patients, since there was always a reason that they did not proceed to surgery. However, the predominant abnormalities were in the temporal lobe in the medically treated control subjects and in the surgical group. Our data present the best available evidence for longterm outcome (in the absence of long-term randomized trials), and are informative on the outcome of two standard strategies for treating patients with drug-resistant partial epilepsy. Except for one 12-month randomized trial, outcome following surgery versus no surgery was determined in nonrandomized cohort and cohort/crosssectional studies. The cross-sectional design may be a limitation because it does not control for potential confounders associated with surgical intervention (e.g., placebo effect), selection bias, or the possible improvement of a nonsurgical control over time when treated in a comprehensive epilepsy center. Alternative study designs using prospective, nonrandomized medical controls or presurgical assessments as controls, however, do not eliminate selection bias or confounding effects potentially associated with surgery. An early study, at a time when medical options were limited, attempted to assess the potential placebo effect of surgery. Although the inclusion of studies as far back as 1947 has obvious

8 1308 D. Schmidt and K. Stavem limitations, the comparison of nonresection surgery and completeness by showing all available studies speak in favor of including early studies. In addition, according to the sensitivity analysis, shown in Table 3, publication data of the study did not appear to influence outcome. The Penfield surgical series from 1947 demonstrated that 5 of 16 patients (32%) of a sham control group who received an exploratory craniotomy without cerebral resection experienced a 50% or higher seizure reduction, but none became seizure-free (Penfield & Steelman, 1947). The series by Ommaya also explored a nonsurgical control group of 25 patients undergoing craniotomy without cerebral resection (Ommaya, 1963). Again, none of the controls became seizure free (Ommaya, 1963). The series from the Bonn University compared seizurefree outcome in three nonsurgical control groups and found clinically important differences in seizure-free outcome (Bien et al., 2006). Patients who were unsuitable for surgery had the highest seizure-free rate of 24%, whereas patients awaiting presurgical assessment or withdrawing from waiting for presurgical assessment had much lower rates of 5% and 14%, respectively (Bien et al., 2006). This study shows that the choice of nonsurgical controls can influence the seizure outcome. In addition, not all patients in the medical and the surgical group were treated with AEDs over the years in the epilepsy center doing surgery; many were treated elsewhere (Moretti Ojemann & Jung, 2006). In addition, we found heterogeneity within surgical and within nonsurgical studies in terms of follow-up including outcome measures used to determine seizure-freedom, reasons for controls not to have surgery, and attrition of patients during long-term follow-up. Furthermore, there was insufficient information to assess the outcome on an intent-treat basis, which would have been desirable given the attrition rate during long-term observations. Also, we could not perform a formal assessment or a ranking of the quality of the studies, and some studies had a difference in follow-up between the surgical and the nonsurgical arms. Finally, there may have been a publication bias, as some of the small studies may not have been published. Although it is important to point out this heterogeneity, we suggest that a comparison of summary outcome of surgery versus nonsurgical treatment may be useful for guidance and long-term evaluation of the net benefit of surgery that has not been evaluated in a large review. Finally, we have not included complications of surgery and of AED treatment or effects of withdrawal of AEDs in patients seizure-free after surgery (Schmidt et al., 2004) in this review, so we cannot provide a long-term risk-benefit analysis of surgery versus drug therapy. The main implications of our results are the following. (1) Surgery is four times as likely as medical treatment alone to transform drug resistance into full drug response resulting in seizure-free outcome. The difference in effect between pooled RR was 42% in favor of surgery. (2) Nevertheless, it is remarkable that seizure-free outcome was observed in 12% of nonsurgical patients by AED treatment alone. This suggests that drug resistance can be overcome by medical treatment in a minority of patients after having experienced lack of seizure control for many years. (3) An important minority of seizure-free surgical patients (but only very few nonsurgical cases) are able to discontinue AEDs. Acknowledgment 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. Disclosure: We have no conflict of interest. References Altshuler L, Rausch R, Delrahim S, Kay J, Crandall P. (1999) Temporal lobe epilepsy, temporal lobectomy, and major depression. 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(2008) Long-term seizures and quality of life after epilepsy surgery compared with matched controls. Neurosurgery 62: ; discussion TØllez-Zenteno JF, Dhar R, Wiebe S. (2005) Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 128: Tellez-Zenteno JF, Dhar R, Hernandez-Ronquillo L, Wiebe S. (2007) Long-term outcomes in epilepsy surgery: antiepileptic drugs, mortality, cognitive and psychosocial aspects. Brain 130: Vickrey BG, Hays RD, Rausch R, Engel J Jr, Visscher BR, Ary CM, Rogers WH, Brook RH. (1995) Outcomes in 248 patients who had diagnostic evaluations for epilepsy surgery. Lancet 346: Wiebe S, Blume WT, Girvin JP, Eliasziw M. (2001) A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 345: Wieser HG, Blume WT, Fish D, Goldensohn E, Hufnagel A, King D, Sperling MR, Lüders H, Pedley TA; Commission on Neurosurgery of the ILAE. (2001) Proposal for a new classification of outcome with respect to epileptic seizures following epilepsy surgery. Epilepsia 42: Yasuda CL, Tedeschi H, Oliveira EL, Ribas GC, Costa AL, Cardoso TA, Montenegro MA, Guerreiro CA, Guerreiro MM, Li LM, Cendes F. (2006) Comparison of short-term outcome between surgical and clinical treatment in temporal lobe epilepsy: a prospective study. Seizure 15: Appendix Literature search strategy 1. First step Epilepsy/surgery [MeSH] OR ( epilepsy [TW] AND surgery [TW]) 2. Second step Incidence [MESH] OR Follow-Up Studies [MESH] OR Prognosis [MeSH:NOEXP] OR prognos* [TW] OR predict* [TW] OR course [TW] OR outcome [TW] OR Survival Analysis [MH:NOEXP] 3. Third step randomized controlled trial [PTYP] OR random* [TW] OR ( double [TW] AND blind* [TW]) OR placebo [TW] OR drug therapy [SH] OR anticonvulsants [SH] OR antiepileptic drugs [SH] OR therapeutic use [SH:NOEXP] OR cohort studies [MESH] OR risk [MESH] OR ( odds [TW] AND ratio* [TW]) OR ( relative [TW] AND risk [TW]) OR case control* [TW] OR case-control studies [MESH] 4. Limits , Human, Journal article

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