Long-term seizure and psychosocial outcomes of epilepsy surgery

Long-Term Seizure and Psychosocial Outcomes of Epilepsy Surgery José F. Téllez-Zenteno, MD, PhD Samuel Wiebe, MD, MSc Corresponding author Samuel Wiebe, MD, MSc Division of Neurology, Foothills Medical Centre, 1403 29th Street NW, Calgary, Alberta T2N 2T9, Canada. E-mail: swiebe@ucalgary.ca Current Treatment Options in Neurology 2008, 10:253–259 Current Medicine Group LLC ISSN 1092-8480 Copyright © 2008 by Current Medicine Group LLC Opinion statement Most results reported in studies focusing on long-term outcomes of epilepsy surgery resemble those reported in studies with shorter follow-up, indicating that many of the surgical results are enduring. In general, about 60% of patients with temporal epilepsy and 25% to 40% of those with extratemporal epilepsy achieve long-term seizure freedom after epilepsy surgery. Over a long term, about 20% of patients discontinue antiepileptic drugs, whereas 41% continue monotherapy and 31% use polytherapy. Evidence concerning the impact of epilepsy surgery on mortality is inconclusive, but some data support a reduction in the risk of death if patients become seizure-free. The information regarding long-term cognitive outcomes is limited but is similar to that derived from short-term studies. Decline in verbal memory occurs frequently after resections of the left temporal lobe; better memory outcomes are reported in seizure-free patients, and memory decline has been documented in patients with intractable epilepsy who do not undergo surgery. However, important confounders such as the effects of antiepileptic drugs, practice effects, and regression to the mean have not been adequately accounted for in these studies. All uncontrolled long-term studies report improved psychosocial outcomes with epilepsy surgery, including employment, education, driving status, satisfaction, and quality of life, but the results of the few existing controlled studies are less persuasive. Introduction Pharmacoresistant epilepsy, a chronic condition with longterm consequences, is often treated with surgery, which produces permanent structural changes and has longlasting effects. Despite the extended time horizon of the condition and the surgical intervention, only in the past two decades have epilepsy surgery centers reported longterm outcomes in cohorts of patients following a variety of surgical interventions. Surgical interventions for epilepsy have not changed dramatically in recent years, so this article focuses on the evidence about long-term outcomes following these well-established surgical interventions. An assessment of the existing evidence reveals signiicant methodologic caveats that inluence the results and their interpretation. There are no randomized, controlled trials (RCTs) with long-term follow-up, which would provide much-needed Class I evidence; such trials admittedly would be dificult to implement. In the absence of RCTs, goodquality, prospective cohort studies with standardized and complete outcome assessment would be desirable. However, an analysis of the available evidence reveals signiicant weaknesses. For example, most reports describe retrospective observations of case series that make them prone to bias and decrease their credibility [1, Class III]. Studies lack standardized outcome descriptions or inconsistently apply outcome classiications such as the Engel classiication [2, Class III]. Centers vary substantially in speciic aspects of 2 Epilepsy 80 Seizure-free patients, % 70 Figure 1. Three rigorous systematic reviews involving short-term, intermediate-term, and long-term seizure outcome report results that are similar for temporal lobe surgery but less favorable in the long term for extratemporal surgery. Temporal epilepsy (T) Extratemporal epilepsy (ET) 60 50 40 30 20 10 0 Engel et al. [7] T = 24 studies; ET = 8 studies Follow-up 1–5 y Téllez-Zenteno et al. [4••] T = 40 studies; ET = 2 studies Follow-up ≥ 5 y McIntosh et al. [1] T = 126 studies Short & long follow-up presurgical evaluation, selection of candidates for epilepsy surgery, and types of surgical procedures used, which adds to the variability of the reported outcomes [3, Class III]. Finally, summarizing the evidence about long-term surgical outcomes requires assessing a plethora of studies, selecting those that meet minimum methodologic criteria, attempting to obtain aggregate estimates of effectiveness that can be used in clinical practice, and exploring possible explanations for observed variations in the results [4••, Class I]. Taking these caveats into account, this review assesses the best available evidence about the long-term outcomes of epilepsy surgery. Most published studies regarding epilepsy surgery focus on seizure outcomes. Studies reporting other important clinical outcomes have been available only during the past 15 years [5••, Class I]. These other topics include antiepileptic drug management, mortality, neuropsychological outcomes, and psychosocial outcomes such as quality of life, satisfaction, driving status, and work status. Because so many publications have reported outcomes of epilepsy surgery (estimated at more than 5000 articles), this analysis focuses on the more scientiically robust studies and systematic overviews synthesizing the evidence. Seizure outcome • The short-term eficacy and safety of epilepsy surgery for temporal lobe epilepsy have been established through a large number of cohort studies (Class III) and one RCT [6, Class I]. In this RCT, patients with temporal lobe epilepsy were randomly assigned to medical or surgical treatment. At the end of 1 year, 58% of patients in the surgical group were free of disabling seizures, compared with only 8% in the medical group. This highly signiicant result (P < 0.0001) yielded a number needed to treat of two, which means that one of every two patients treated surgically will be rendered seizure-free. However, this study was limited to outcomes at 1 year. • In 2003, Engel et al. [7, Class I] synthesized the evidence about epilepsy surgery with an intermediate duration of follow-up (1 to 5 years) in a meta-analysis of 32 studies involving 2250 patients (Fig. 1). In the aggregate, 65% of patients with anteromesial temporal resections were seizure-free, 21% improved, and 14% did not improve. A subanalysis of that study found that outcomes were similar in patients with 2 to 5 years of follow-up: 63% (95% CI, 60%–66%) remained seizure-free. Evidence for extratemporal surgery was weaker, and management recommendations were less certain. • In another systematic review of temporal lobe resections [1, Class III], seizure-free rates varied widely (33%–93%), with a median of 70% (Fig. 1). • Téllez-Zenteno et al. [4••, Class I] recently synthesized the evidence about outcomes of epilepsy surgery after 5 years or longer (Fig. 1). Table Long-Term Outcomes of Epilepsy Surgery Téllez-Zenteno and Wiebe Table 1. Median proportion of seizure-free patients ≥ 5 years after epilepsy surgery Type of surgery Seizure-free patients, % (95% CI) Temporal lobe resection 66 (62–70) All extratemporal resections 34 (28–40) Frontal lobe resection 27 (23–30) Parietal and occipital lobe resections 46 (35–57) Multiple subpial transections Callosotomy 16 (8–24) 35 (26–44)* *Free of seizures causing falls. (Data from Téllez-Zenteno et al. [4••].) 1 shows the median proportion of seizure-free patients in the long term, divided by type of surgery. Methodologic issues highlighted by this meta-analysis include the lack of controls in most studies and the lack of standardization in assessing and reporting outcomes. In contrast to the reports by Engel et al. [7, Class I] and McIntosh et al. [1, Class I], TéllezZenteno et al. [4••, Class I] found that the rate of long-term freedom from seizures was somewhat lower in studies with very long follow-up (> 10 years). However, the most salient inding was that overall, longterm outcomes were consistently similar to those of short-term studies, including those from the 1-year RCT [6, Class I]. • The most recent studies exploring long-term outcomes following resective epilepsy surgery report seizure-free rates very similar to those reported in the meta-analysis by Téllez-Zenteno et al. [4••], such as 72% at 10 years [8, Class III] and 65% at 12 years [9, Class III]. Thus, the evidence supports the notion that the beneits of surgery are generally durable. Use of antiepileptic drugs • Schmidt and Löscher [10, Class III] reviewed the use of antiepileptic drugs (AEDs) after temporal lobe epilepsy surgery with short-term and long-term follow-up, emphasizing the proportion of “cured” patients (seizure-free and off AEDs). Approximately one third of patients were cured, one third were controlled on AEDs, and one third continued to have disabling seizures on AEDs. • Téllez-Zenteno et al. [5••, Class I] performed a second meta-analysis of long-term surgical outcomes, exploring the use of AEDs. Their indings were somewhat less favorable than those of Schmidt and Löscher [10]. For all types of surgery, in the long term 22% (95% CI, 18%–23%) were cured and 20% (95% CI, 18%–23%) were off AEDs (with or without seizures); 41% (95% CI, 37%–45%) were on monotherapy and 31% (95% CI, 27%–35%) were on polytherapy. Outcomes with regard to AEDs varied by type of surgery: after temporal lobe surgery, 20% (95% CI, 17%–23%) were cured, 14% (95% CI, 11%–17%) were free of AEDs, 50% (95% CI, 45%–55%) were on monotherapy, and 33% (95% CI, 29%–38%) were on polytherapy. In the subgroup of studies reporting results in controls (possible surgical candidates who did not have surgery), 0% of patients were off AEDs or cured, 24% (95% CI, 15%–32%) were on monotherapy, and 75% (95% CI, 66%–83%) were on polytherapy. • It is essential to point out that published data can only be interpreted as a depiction of particular practice patterns in selected groups of patients. Practices regarding decreasing or discontinuing AEDs after surgery vary widely because there are currently no standards of practice or evidence 3 4 Epilepsy guides. Existing studies are not designed to capture the effect of surgery on AED requirements, so this remains an unanswered question awaiting assessment in an RCT. • Controlled studies assessing AED use are few and results vary. For example, Schiller et al. [11, Class II] retrospectively evaluated seizure outcomes pertaining to AEDs following successful epilepsy surgery. In patients who discontinued AEDs, seizures recurred in 26% at 5 years, compared with 7% of those who did not discontinue AEDs. • By contrast, in a prospective controlled study by Berg et al. [12•, Class I], paradoxically, seizures recurred in 32% of those who decreased or stopped AEDs and in 45% of those who did not, a statistically signiicant difference. The most important predictor of seizure freedom, regardless of AED use, was immediate remission after surgery. • Clearly, RCTs are needed to assess the impact of surgery on AED use. Nonetheless, current practice descriptions indicate that in the long term and for all types of surgery, about 20% of patients are seizure-free and off AEDs, and 20% to 30% are seizure-free but still taking AEDs. Mortality • The ultimate outcome, mortality, greatly concerns patients and physicians [13, Class III]. Studies from the community and in selected populations consistently point to an increased risk of death in epilepsy. In hospitals or epilepsy centers, the standardized mortality ratio (SMR) ranges from 1.9 to 3.6 [14–16, Class II and III]. In population-based studies, the SMR ranges from 1.6 to 4.1 [17, Class III]. • Few studies have analyzed mortality after epilepsy surgery and the results are not consistent. In the short term, a decrease in mortality has been reported. Salanova et al. [18, Class II] found that patients with persistent seizures following temporal lobe surgery had an SMR of 7.4, compared with 1.7 (similar to the general population) in those who became seizurefree. On the other hand, Nilsson et al. [15, Class II] did not ind a trend toward decreased mortality in patients rendered seizure-free by surgery. • In their systematic review, Téllez-Zenteno et al. [5••, Class I] identiied only six studies assessing mortality in the long term (> 5 years). Of three studies comparing mortality in surgical versus nonsurgical patients [19•,20,21, Class II], two found no difference [19•,21, Class II], and one found reduced mortality in surgically treated patients [20, Class II]. This divergence of results may be explained by differences in methods and study populations. For example, studies use different metrics to assess mortality rates and, most importantly, seizure outcomes, resulting in noncomparable populations. • The same systematic review identiied a group of studies in which mortality was assessed according to a more similar seizure status, and mortality was compared between surgery patients and the general population [5••, Class I]. Hennessy et al. [22, Class II] found that epilepsy surgery did reduce mortality, but not quite to the rate of the general population. Salanova et al. [18, Class II] and Sperling et al. [23, Class II] compared surgically treated patients who were seizure-free with those who were not seizure-free; the mortality rate was reduced in the seizure-free patients. • In summary, the available information suggests—but does not prove— that epilepsy surgery reduces the risk of death in the long term. Long-Term Outcomes of Epilepsy Surgery Téllez-Zenteno and Wiebe Cognitive function • Chronic epilepsy is often accompanied by cognitive changes and by alterations of processes related to functional reorganization and behavioral compensation. Poor cognitive function is generally associated with early onset and long duration of epilepsy and with poor seizure control [24, Class III]. Nevertheless, patients who may beneit from epilepsy surgery may be deterred from it because of concerns about postoperative cognitive decline. Reports of short-term outcomes show that cognition remains relatively stable following right temporal lobe resection and that verbal memory decline is commonly observed after left temporal resection. However, the deicit may be mitigated to some extent by good seizure outcome [25, Class II]. • Few studies have assessed long-term cognitive outcomes after surgery. One of the more robust observations regarding cognitive outcome in the long term is that of Helmstaedter et al. [26, Class II]. This controlled study of 249 patients found that memory decline was more prominent in patients with left temporal lobe resections, but seizure-free patients were least affected and surgery did not affect intelligence. Importantly, this study also suggests that patients not undergoing surgery have signiicant cognitive decline over time. Although this study does not adequately account for practice effects and the effects of AEDs on cognitive function, it does raise important considerations and points the way for future analyses. • Téllez-Zenteno et al. [5••, Class I] uncovered only six studies exploring long-term postoperative cognitive function. Four studies evaluating intelligence in patients with temporal lobe resections found no changes [27–30, Class III]. Three studies exploring memory function in patients with temporal lobe resections yielded inconsistent results. Helmstaedter et al. [26, Class II] and Paglioli et al. [31, Class II] found verbal memory decline following left temporal lobe surgery, in agreement with shortterm follow-up studies [25, Class III]. On the other hand, Alpherts and colleagues [32, Class II] recently evaluated neuropsychological outcomes in 85 patients who underwent temporal lobe resection. They found greater decline in verbal memory in patients with left temporal resections who also had mesial temporal sclerosis (MTS), as compared with those without MTS. Unlike other investigators, however, they found no improvement in memory in seizure-free patients. Kirkpatrick et al. [30, Class II] found no differences in memory function following either right or left temporal resection. This is probably explained by the select nature of their patients, all of whom had tumor-related epilepsy surgery. • In summary, information on long-term cognitive outcomes is scanty; results are similar to those in short-term reports, but they are only partly consistent. Left temporal resections have a higher risk of postoperative verbal memory impairment, and seizure freedom may entail better memory outcomes. However, future studies need to carefully assess possible confounders such as practice effects, cognitive effects of AEDs, the type and extent of surgery, and the duration of follow-up. Psychosocial outcomes • Individuals with refractory partial epilepsy suffer from signiicant psychosocial impediments, including inability to drive, employment restrictions, stigma, dificulties with family function, and general worsening of the quality of life, accompanied by health deterioration [33,34, Class III]. Social outcomes are seldom reported in studies of epilepsy 5 6 Epilepsy surgery, and little information exists regarding long-term outcomes [34, Class III]. Téllez-Zenteno et al. [5••, Class I] identiied 11 studies reporting long-term postoperative psychosocial outcomes [31,35–44, Class III]. All were case series without controls, and all but two focused on temporal lobe epilepsy; one dealt with callosotomy [41, Class III] and one with hemispherectomy [39, Class III]. All the studies reported positive psychosocial outcomes after surgery, including better employment status [31,35,40,41,43,44, Class III], quality of life [37,40,44, Class III], improved ability to drive [42,44, Class III], improved educational status [31,35,39,40,44, Class III], and satisfaction with outcomes of epilepsy surgery [39, Class III]. Another recent, noncontrolled study described improvement in various psychosocial outcomes [45, Class III]. • The absence of controls in these studies detracts from the validity of the results and precludes any irm inferences about the true effects of surgery. It is highly probable that the reported beneits are inlated to a considerable degree. For example, one of two controlled studies with long-term follow-up [26, Class II] found improvement in some areas (quality of life and depression) but not in others (social aspects). The other controlled study found no differences in social outcomes or quality of life [20, Class II]. Future research • Data on long-term outcomes of epilepsy surgery are essential to help us understand not only the effects of these interventions but also the course of illness in this group of patients. Agreement on methodologic standards is essential to reduce the large variability in methods and results seen in the literature. • The ideal long-term outcome study would involve randomized, controlled comparisons of surgically and medically treated patients. Longterm RCTs are generally not feasible unless studies focus on surgical interventions that are not considered to be standard therapy and for which true equipoise persists for a long time. Acceptable alternative sources of evidence must be used, including well-designed prospective cohort studies with systematic, preplanned outcomes—preferably independently assessed—and with nonrandomized, concurrent, controlled comparisons of similar patients not having surgery. These types of studies are sparse. Disclosures No potential conlicts of interest relevant to this article were reported. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2. McIntosh AM, Wilson SJ, Berkovic SF: Seizure outcome after temporal lobectomy: current research practice and indings. Epilepsia 2001, 42:1288–1307. Engel J, Van Ness PC, Rasmussen TB: Outcome with respect to epileptic seizures. In Surgical Treatment of the Epilepsies, edn 2. Edited by Engel J Jr. New York: Raven Press; 1993:609–621. 3. Spencer SS: Long-term outcome after epilepsy surgery. Epilepsia 1996, 37:807–813. 4.•• Téllez-Zenteno JF, Dhar R, Wiebe S: Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005, 128:1188–1198. 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