Surgical versus medical treatment for refractory ... - Stem Cells Journals

CRITICAL REVIEW AND INVITED COMMENTARY

Surgical versus medical treatment for refractory epilepsy: Outcomes beyond seizure control *M. Scott Perry and †‡Michael Duchowny Epilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

SUMMARY

Dr. Perry is the Medical Director of the EMU at Cook Children’s Medical Center in Ft. Worth, Texas.

Nearly one third of patients with epilepsy become medically intractable, and the likelihood of achieving seizure freedom decreases with each additional medication trial. For appropriately chosen patients, epilepsy surgery affords the opportunity to achieve seizure freedom and potentially wean off medications. Epilepsy surgery, as with medical management, is not without adverse effects; to counsel patients wisely, practitioners need to understand the advantages and disadvantages of both. Randomized controlled trials in temporal lobe epilepsy reveal that epilepsy surgery achieves superior outcome compared to continued medical management. Although seizure freedom is the ultimate goal of any therapy, it represents a single outcome measure among a variety of other domains that affect patient welfare. It is imperative that providers understand the patient variables that affect these outcome measures and how these measures impact each other. Because the data comparing surgical therapy versus medical management for refractory epilepsy are limited, we review the available evidence comparing outcomes beyond seizure freedom including quality of life, cognition, psychosocial function, mortality, and financial costs. KEY WORDS: Quality of life, Cognition, Psychosocial function, Mortality, Costs, Refractory epilepsy.

Up to one third of patients with epilepsy become medically intractable, defined as failure of two appropriately chosen and dosed antiepileptic drugs (AEDs), and have minimal chances of seizure freedom on subsequent medication trials (Kwan & Brodie, 2000). As a result, patients with medically intractable epilepsy are increasingly referred for epilepsy surgery in the hopes of achieving immediate and lasting seizure control. In a randomizedcontrolled trial (RCT) of surgical versus medical management, Wiebe et al. (2001) demonstrated superior rates Accepted September 18, 2013. *Comprehensive Epilepsy Program, Jane and John Justin Neuroscience Center, Cook Children’s Medical Center, Fort Worth, Texas, U.S.A.; †Department of Neurology and Brain Institute, Miami Children’s Hospital, Miami, Florida, U.S.A.; and ‡Department of Neurology, University of Miami Leonard Miller School of Medicine, Miami, Florida, U.S.A. Address correspondence to M. Scott Perry, 4th Floor, 1500 Cooper Street, Fort Worth, TX 76104, U.S.A. E-mail: scott.perry@cookchildrens. org Wiley Periodicals, Inc. © 2013 International League Against Epilepsy

of seizure freedom among patients undergoing temporal lobectomy compared to patients who continued medical treatment for intractable temporal lobe epilepsy (TLE). In the same study, improvements in quality of life (QOL), rates of employment, and school attendance were seen within the surgical group, suggesting favorable outcomes in addition to seizure control. Beyond this single RCT, there is a paucity of class I outcomes data that compares medical to surgical management. This is not surprising, as formidable obstacles exist to such research, including the heterogeneity of clinical presentation by age, etiology, and epilepsy type. Likewise, there are ethical implications to delaying surgical therapy in select populations. For example, certain pediatric epileptic encephalopathies are especially amenable to surgical therapy and any delay in definitive treatment may result in further brain damage (Shields, 2000). It has also been shown that a shorter interval from seizure onset to surgical intervention is associated with greater epilepsy severity (Baca et al., 2013). Similarly, in adult populations, duration of TLE cor-

2060

2061 Surgical versus Medical Treatment of Epilepsy relates with structural atrophy within and beyond the temporal lobe, which may have implications for outcomes if treatment is overly delayed (Bernasconi et al., 2005; Coan et al., 2009). Despite these limitations, there is great value in comparing medical to surgical therapy for refractory epilepsy and much can be gained by reviewing cohort and crosssectional cohort studies related to this topic. To provide the most comprehensive counseling to patients and their families, it is also important to understand the impact of treatment beyond seizure control, including costs of therapy, QOL, cognitive and psychological function, and mortality. It is also essential to understand how patient characteristics impact these outcomes. For example, early surgical therapy may have considerable implications for cognitive development in childhood-onset epilepsy, but less for adults, whereas the impact on independent living is often far different within an adult population. Spencer and Huh (2008) reviewed epilepsy surgery as treatment in both adult and pediatric populations, specifically examining outcomes of seizure freedom, QOL, mortality, cognition, and psychiatric comorbidities. This review provides an excellent understanding of the impact that successful epilepsy surgery has on multiple outcome domains, but did not review or compare outcomes when medical treatment was used in lieu of surgical therapy. Other studies have specifically examined one or more of these outcome variables in relationship to medical management, surgical therapy, and in rare cases, comparison between both treatment options. In the present manuscript, we sought to review and compare outcomes following treatment of refractory epilepsy with either medical management or surgical therapy. We review the available literature for both pediatric and adult populations and discuss the impact that characteristics of each population have on choice of therapy. When available, studies directly comparing these therapeutic approaches with respect to outcome are reviewed (Table 1). In addition to seizure control, we examine data that compare costs of treatment, mortality, cognitive development, and psychosocial outcome between these two treatment groups. The authors performed literature review utilizing the PubMed online database. Searches for relevant articles were performed using terms “intractable epilepsy,” “refractory epilepsy,” “outcome,” “medication or medical treatment,” “surgery,” “quality of life,” “costs,” “psychosocial,” “cognition,” and “mortality,” both alone and in combination. All article types were included in the search. The authors reviewed all studies and identified articles related to the topic under study, and then reviewed additional articles cited within those studies as warranted. Only articles written in English were included in this review.

Seizure Control in Medically versus Surgically Treated Patients with Chronic Focal Epilepsy Although there are a variety of outcomes to consider following therapy for refractory epilepsy, none are regarded as important as seizure freedom. The effect of seizure freedom on other domains discussed in this review confirms this point. Surgical therapy is now regarded as demonstrably superior to chronic medical management based on an RCT of adults with intractable TLE (Wiebe et al., 2001). This study, made ethically possible by a 1-year waiting period for patients approved for surgical therapy, compared seizure-free outcome at 1 year after temporal lobectomy to continued medication trials. Fifty-eight percent of patients in the surgical arm were seizure-free at 1 year compared to only 8% in the medical management group. This was followed by an RCT comparing early surgery in TLE to continued medical management (Engel et al., 2012). In this study, terminated early because of slow accrual, 11 of 15 patients treated with temporal lobectomy were seizure-free at 2 years compared to none of 23 patients on medical management. Although these studies convincingly support the superiority of surgical therapy in appropriately chosen candidates, the cohorts were restricted to patients with TLE and thus limit application of the data to the wide variety of refractory epilepsy phenotypes. Several observational cohort and cross-sectional studies investigated outcome between surgically treated epilepsy and nonoperated patients. Schmidt and Stavem (2009) performed a meta-analysis of 20 such studies (19 nonrandomized), of which 17 included only patients undergoing temporal lobe procedures. Nonrandomized studies are subject to bias and the choice of control groups are not always equivalent (i.e., patients deemed not surgical candidates, patients refusing surgical therapy, or patients awaiting surgery). Nonetheless, 44% of patients treated with surgical therapy were seizure-free compared to 12% of medically treated patients, with more surgical patients (36%) off AEDs completely, supporting the findings of the randomized trials. Choi et al. (2008) used a Monte-Carlo decision analysis to compare surgical therapy to medical management and demonstrated that medical management would be superior only in unlikely conditions (i.e., mortality of surgery >24%, annual probability of remission with medication >79%, and low rate of disabling seizures on medication alone). There are no studies that directly compare extratemporal lobe surgery to medical management, thus inferences about the comparative efficacy of treatments for extratemporal lobe epilepsy cannot be made. It is important to note that 12% of the patients treated medically in the meta-analysis of Schmidt and Stavem Epilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

2062 M. S. Perry and M. Duchowny Table 1. Summary of selected studies comparing medical to surgical management for intractable epilepsy Authors

Study design

Patient population

Seizure freedom Wiebe et al. (2001)

RCT

Primarily adult (>16 years)

Engel et al. (2012)

RCT

Primarily adult (>12 years)

Schmidt and Stavem (2009)

Meta-analysis

Adult and pediatric

Chen et al. (2002)

Retrospective observational case-control

Pediatric

Prospective observational case-control

Pediatric

Helmstaedter et al. (2003)

Prospective case-control

Adult

Smith et al. (2004)


Pediatric

Observational case-control

Pediatric

Smith et al. (2004)


Pediatric

Guldvog et al. (1991a,b)

Retrospective case-control

Adult

Mikati et al. (2010)


Pediatric

Cognition Skirrow et al. (2011)

Psychosocial Smith et al. (2011)

Key findings At 1 year, patients free of seizures impairing awareness was 58% for surgical patients and 8% for medical management At 2 years, 0 of 23 patients in the medical group and 11 of 15 patients in the surgical group were seizure-free 719 (44%) of 1,621 surgery patients compared to 139 (12%) of 1,113 nonoperated controls achieved seizure freedom Medical management resulted in seizure freedom in 12% of patients No difference in seizure-free outcome between medical management and surgery at 1–4 years Focal lesions on MRI are a poor predictor of medication response Patients with focal lesions did better after surgical therapy Full-scale IQ improved in patients after surgery for TLE compared to controls Realization of IQ improvements took up to 6 years Both surgical and medical management results in memory decline in patients with TLE Surgery patients may decline more if surgery is unsuccessful, especially if performed on the left temporal lobe Seizure-free patients have improvement in memory and nonmemory function No significant improvement in cognitive function was present 1 year post–epilepsy surgery, regardless of seizure freedom Patients seizure-free after surgery were significantly less like to report symptoms of psychological distress compared to patients having seizures after surgery or those treated with medication alone No improvement in social, emotional, or behavioral function was demonstrated at 1 year post-op compared to medical management Patients treated with surgery were more likely to report that treatment improved their working ability Significant improvements in work status were seen only in those with higher education or those working pretreatment Surgery patients and medical patients had worse total QOL compared to healthy controls preoperatively Patients seizure-free postoperatively did not differ from healthy controls in any domain of quality of life Continued

Epilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

2063 Surgical versus Medical Treatment of Epilepsy Table 1. Continued. Authors Mortality Bell et al. (2010)

Study design

Patient population

Key findings

Retrospective case-control

Adult

Nonoperated patients were 2.4 times more likely to die and 4.5 times likely to die of epilepsy-related cause Operated patients with seizures post-op were 4 times more likely to die compared to those seizure-free post-op

Decision analysis

Pediatric

Widjaja et al. (2011)

Decision analysis

Pediatric

Langfitt et al. (2007a)


Adult

Initial costs are greater for surgical therapy Surgery becomes more cost-effective 14 years after therapy, especially in seizure-free patients Surgical treatment resulted in positive monetary benefit compared to medical management at 1 year post-op Two years after evaluation, patients seizure-free post-op have substantially less healthcare costs compared to nonoperated patients and patients who continue to have seizures post-op

Costs Keene and Ventureya (1999)

(2009) became seizure-free, highlighting the possibility of response to medical therapy even in patients diagnosed with refractory epilepsy. The tendency of refractory epilepsy to spontaneously remit or respond to medication has been reported previously (Selwa et al., 2003; Luciano & Shorvon, 2007; Neligan et al., 2011). In a study of adult patients with refractory epilepsy, 30% entered into periods of seizure remission lasting at least 2 years (Neligan et al., 2011). Patients who remitted had less frequent seizures prior to remission, although no other variables predicted which patients would achieve this outcome. Additional medication trials or optimization of medication may also result in seizure freedom. The introduction of a new AED produced seizure freedom in 16% and worthwhile improvement in 21% of patients with apparent intractable epilepsy (Luciano & Shorvon, 2007). Similarly, a study in children demonstrated that titrating AEDs to maximum tolerable doses can result in seizure freedom in 10% of cases (Gilman et al., 1994). There are limited data comparing medical to surgical management in children. The data that are available lack the rigorous randomized prospective design of the adult studies by Wiebe et al. (2001) and Engel et al. (2012). As a result, the populations studied are heterogeneous, with a variety of secondary variables that may influence outcome. Widjaja et al. (2011) performed a cost analysis comparing 15 randomly chosen pediatric patients who underwent excisional surgery for intractable epilepsy to 15 patients who continued medical management. Nine surgically treated patients were seizure-free compared to only three patients treated medically, with surgically treated patients experiencing a 42% greater reduction in seizure frequency.

Mikati et al. (2010) reported that 79% of patients remained seizure-free 2 years after surgery compared to only 21% of nonoperated controls with intractable epilepsy. As in the adult cohorts, control groups were not equivalent, as many patients were not suitable surgical candidates due to poor localization of the epileptogenic zone. Chen et al. (2002) found no significant differences in seizure-free outcomes in a pediatric cohort when comparing surgery to medical therapy. However, the majority of patients in the medical arm had previously received care from primary care providers and responded to adjustments in therapy only after being evaluated by epilepsy specialists. Patients with focal lesions in the medical group responded poorly to medication changes, whereas comparable patients in the surgical group responded favorably. Although beyond the scope of this review, several preoperative and perioperative variables contribute to predicting seizure freedom (Table 2) and should be considered when evaluating potential surgical candidates. Many variables are ultimately related to the ability to achieve complete resection of the epileptogenic zone. Complete resection is the only predictor of postoperative seizure freedom, which is repeatedly supported in the literature regardless of histopathologic etiology (Paolicchi et al., 2000; Bilginer et al., 2009; Guilioni et al., 2009; Krsek et al., 2009; Chang et al., 2011; Rowland et al., 2012). Localization of the epileptogenic zone relies on accurate characterization of the anatomic lesion with anatomic and functional imaging, along with complete localization of the physiologic lesion by electrophysiology. Patients with complete resection of both the anatomic and physiologic epileptogenic zone are most likely to be rendered seizureEpilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

2064 M. S. Perry and M. Duchowny Table 2. Preoperative and perioperative variables that may predict seizure-free outcome following epilepsy surgery Preoperative variables Older age at seizure onset (Cossu et al., 2008) Unifocal lesions on MRI (Cossu et al., 2008; Perry et al., 2010; Yang et al., 2011) Psychiatric comorbidities (Guarnieri et al., 2009; Kanner et al., 2009) IQ > 70 (Malmgren et al., 2008) Temporal lobe onset (Yang et al., 2011; Rowland et al., 2012) Operative variables Completeness of resection (Paolicchi et al., 2000; Bilginer et al., 2009; Guilioni et al., 2009; Krsek et al., 2009; Rowland et al., 2012) Unilobar resections (Wyllie et al., 1998; Cossu et al., 2008; Perry et al., 2010) Temporal lobe resections (Wyllie et al., 1998; Alexandre et al., 2006; Cossu et al., 2008)

free, although patients with complete resection of either the anatomic or physiologic lesion achieve seizure freedom in up to 50% of cases (Perry et al., 2010). When incomplete resection of both the anatomic and functional zones is inevitable, seizure freedom is unlikely. In summary, the available evidence convincingly demonstrates that patients with intractable focal epilepsy have a higher likelihood of seizure freedom following an excisional surgical procedure, and that surgical therapy is superior compared to continued trials of medication. However, these data do not address epilepsy outside the temporal lobe and it is unlikely that further RCTs will be possible. Instead, prospective study of eligible surgical patients who elect to defer surgical therapy will likely provide the most useful surgical controls for future research.

Does Surgical Therapy Result in Improved Cognitive Status Compared to Medical Treatment? Seizures adversely impact cognitive development. Although several factors likely contribute to the lower cognitive trajectory, the intrinsic pharmacoresistance of epilepsy and the onset of seizures in early life are of particular importance. In a prospective cohort study of children with epilepsy diagnosed before 8 years of age, early age of onset and pharmacoresistance resulted in lower full-scale intelligence quotient (IQ) (Berg et al., 2012). The impact of pharmacoresistance was most profound in infancy (0–3 years), although in the absence of pharmacoresistance, age of onset did not affect outcome. These findings argue for early aggressive treatment to achieve seizure control in infants and young children with intractable epilepsy. Cognition in medically intractable TLE is especially vulnerable to repeated seizures. Anatomic studies in this clinical cohort reveal progressive atrophy of both gray and white matter structures. Atrophy correlates with duration of epilepsy and seizure frequency, particularly seizures of left hemisphere onset (Bernasconi et al., 2005; Coan et al., 2009; Kemmotsu et al., 2011). Prenatal and early acquired dominant temporal lobe lesions also disrupt receptive and expressive language networks (Korman et al., 2010). Early Epilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

childhood-onset TLE reduces brain volume, particularly white matter tracts, leading to reduced cognitive function (Hermann et al., 2002). The impact of early onset chronic TLE was confirmed in a retrospective study of adult patients with medically intractable childhood-onset TLE (Baxendale et al., 2010). Deficits in verbal learning and recall were established in childhood but subsequently declined, albeit from a lower baseline similar to the general population (Baxendale et al., 2010). Even the later onset of pharmacoresistance is not without cognitive impact. The presence of newly diagnosed epilepsy in adulthood impairs memory, psychomotor speed, and higher executive function 1 year after diagnosis compared to healthy controls (Baker et al., 2011). Establishing pharmacoresistance in adulthood more commonly impacts attention/processing and visual/verbal memory domains compared to childhood seizure onset in which verbal comprehension and perceptual organization are affected more dramatically (Hermann et al., 2006; Taylor & Baker, 2010; Berg et al., 2012). Seizure control is believed to improve cognition and protect from further regression. Although both surgical and medical treatment can achieve this goal, they both are associated with adverse effects that also impair outcome. For example, seizure freedom may be possible with high serum concentrations of AEDs only, thereby causing additional cognitive complications. Likewise, surgical therapy may produce seizure freedom but anatomically disrupt neural networks necessary for cognitive processing. Helmstaedter et al. (2003) examined memory and nonmemory functions in a longitudinal study comparing adult patients with intractable epilepsy who were undergoing temporal lobectomy to patients who were managed medically. Both the medically and surgically treated groups experienced memory decline, whereas nonmemory function remained stable. Seizure-free patients, more commonly treated with surgery, were more likely to recover memory and nonmemory function over time. Seizure control and a higher baseline cognitive status were predictors of more favorable outcome. Although surgery improved cognition after seizure freedom, surgical failure, particularly after left-sided resections, accelerated memory decline.

2065 Surgical versus Medical Treatment of Epilepsy Skirrow et al. (2011) compared the long-term cognitive follow-up of children undergoing temporal lobectomy to patients on medical management owing to discordant presurgical data. Patients treated surgically evidenced improvement in their full-scale IQ, but not do so until 6 years after therapy. Patients with low preoperative IQs demonstrated the most significant postoperative improvements. Although both cognitively impaired and high-functioning children may benefit from seizure reduction after surgery, high-functioning patients are at higher risk for postoperative declines (Freitag & Tuxhorn, 2005). Patients undergoing hemispherectomy for intractable childhood epilepsies experience improvements in both motor and language development, particularly if seizure freedom is achieved early on (Jonas et al., 2004; Lettori et al., 2008). Conversely, Smith et al. (2004) did not find a significant change in cognitive status 1 year after epilepsy surgery in pediatric patients when compared to patients who were medically managed, despite many achieving seizure freedom. However, the authors note that the duration of followup may not have been adequate to assess for cognitive change and all patients in this study remained on AEDs. Improvements in cognitive outcome are strongly correlated with cessation of AEDs (Skirrow et al., 2011), thus representing a potential advantage of surgical therapy over medical management. Limited evidence from both controlled and uncontrolled studies suggests that successful epilepsy surgery, defined as complete seizure freedom, has the potential to improve cognitive function. However, improvements in cognition are not absolute following epilepsy surgery, even in cases in which seizure freedom is achieved, and some cognitive improvements may take years to manifest. Medical management also offers potential for improved cognition, but the opportunity to completely wean from AEDs in surgically treated patients is an added bonus, as it often results in additional cognitive improvement. However, unsuccessful epilepsy surgery may accelerate existing dysfunction or produce new dysfunction that may not have otherwise occurred.

Compared to Medical Therapy Does Surgical Therapy Reverse Psychosocial Deterioration in Chronic Focal Epilepsy? The unpredictable nature of epilepsy and its associated stigma impart a variety of psychosocial difficulties including lower educational status, underemployment or unemployment, lower socioeconomic status, decreased rates of marriage, and increased rates of psychological morbidity. These are a few of many factors that ultimately contribute to the measurement of QOL in patients with epilepsy.

In a large Dutch cohort with newly diagnosed epilepsy followed for >30 years, rates of marriage, learning achievement, and employment status were lower compared to that in the general population (Shackleton et al., 2003). The impact was more pronounced in childhood-onset epilepsy, particularly in individuals who require continuing medication, regardless of seizure control. Lower rates of employment, marriage, and driving were reported in a Finnish cohort of childhood-onset epilepsy that was not intractable, and psychosocial outcome was most influenced by use of AEDs, regardless of seizure-free state (Sillanp€a€a et al., 1998, 2004). This is not to say that seizure control does not improve QOL, as seizure-free patients who continue medication report fewer comorbid conditions and more positive health outcomes (Shackleton et al., 2003). The effect of seizure freedom on quality of life may be equally if not more important than continued requirement for AEDs in patients with medically intractable epilepsy (Spencer et al., 2007; Seiam et al., 2011). Few studies directly compare the impact of medical management and surgical therapies on QOL. In an RCT that compared epilepsy surgery to medical management, Wiebe et al. (2001) found statistically significant improvement in QOL among patients treated with temporal lobectomy compared to medical management. Although a larger proportion of surgery patients obtained jobs and were attending school, this difference did not reach significance. A recent study examining QOL in adult patients deemed unacceptable for epilepsy surgery or who chose not to undergo epilepsy surgery, demonstrated significantly lower QOL scores compared to operated patients (Elsharkawy et al., 2012). Tolerability and efficacy of AEDs, seizure frequency, and employment status were the main determinants of favorable QOL. Other adult studies have focused primarily on preoperative versus postoperative QOL, demonstrating the positive impact of surgical therapy. Seiam et al. (2011) reviewed 32 studies of QOL in epilepsy surgery patients and found 29 studies (90%) that showed a significant positive effect on at least one QOL domain. Preoperative psychological function, measured as preexistence of psychological morbidity or unfavorable validated measurements of psychosocial function, was the most important preoperative predictor of poor QOL outcome postoperatively. In fact, mood is a major contributor to QOL in epilepsy patients (Perrine et al., 1995). Postoperative psychiatric disease most often improves or remains unchanged in seizure-free patients, although worsening or de novo psychiatric disease may occur in patients who continue to experience seizures (Macrodimitris et al., 2011). It is not surprising that seizure outcome is the most important postoperative predictor of improved QOL, regardless of the treatment used—patients who become seizure-free show a threefold increase in overall QOL compared to those who experience seizure reduction only (Gilliam, 2003; Seiam et al., 2011). However, the impact of seizure frequency on Epilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

2066 M. S. Perry and M. Duchowny QOL among patients with uncontrolled epilepsy is less clear (i.e., do daily seizures impact QOL more than weekly seizures? Gilliam, 2003). Other studies found no significant relationship between postoperative seizure outcome and QOL (Dupont et al., 2006). Patients with unrealistic preoperative expectations or postoperative functional deficits in addition to continued seizures may evidence a decline in QOL (Wilson et al., 1998; Langfitt et al., 2007b). QOL in patients with intractable epilepsy can also improve with continued medical management. Patients rejected for epilepsy surgery may still experience significant improvement in QOL, typically related to spontaneous seizure remission (Selwa et al., 2003). Granted, spontaneous remission occurs in only 20–30% of patients and is more commonly encountered in patients with infrequent seizures (Selwa et al., 2003; Neligan et al., 2011), but the incidence is far from negligible. Patients with intractable epilepsy who enter remission often relapse and are thus rarely afforded the opportunity to become medication free (Schmidt & Stavem, 2009; Neligan et al., 2011). Because the continued use and adverse effects of medication are also major contributors to QOL (Gilliam et al., 1999; Gilliam, 2002), this suggests that surgical therapy resulting in seizure freedom and medication freedom will produce superior QOL outcomes. Similar to the adult experience, few studies directly compare the impact of surgical therapy to medical management on QOL for children with intractable epilepsy. Mikati et al. (2010) compared a group of pediatric patients who underwent epilepsy surgery to controls with intractable epilepsy who were not surgery candidates and healthy individuals. Although nonsurgical patients were poor surgery candidates and thus not truly matched for disease state, surgery patients had better behavioral outcomes compared to nonsurgery patients, and the QOL of patients who were rendered seizure-free postoperatively were similar to healthy controls. Smith et al. (2011) compared psychological well-being between seizure-free pediatric epilepsy surgery patients, patients with postoperative seizures, and patients on medical therapy for intractable epilepsy. They found a modest advantage in psychological well-being for seizure-free patients, but failed to demonstrate any advantage for symptoms of depression or anxiety compared to nonsurgical patients. Another study comparing medical management to epilepsy surgery in children failed to demonstrate any advantage of either therapy on behavior, emotional, or social functioning, except in cases in which epilepsy surgery was performed at an early age (Smith et al., 2004). Improvements in QOL have been demonstrated in patients undergoing hemispherectomy compared to nonsurgical patients, with continued seizures and higher AED load predicting less favorable QOL (Griffiths et al., 2007). Other studies have specifically compared QOL before and after epilepsy surgery only (Van Empelen et al., 2005; Sabaz et al., 2006; Benifla et al., 2008). Postoperatively, Epilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

patients more often become employed or attended school (Benifla et al., 2008) and there are improvements in social competence, athletic competence, and emotional relationships (Van Empelen et al., 2005). As noted in adults, seizure freedom in children is also a major contributor to improved QOL following epilepsy surgery (Sabaz et al., 2006; Benifla et al., 2008). Seizure freedom is pivotal to gains in QOL after epilepsy surgery in both adults and children. Patients with intractable epilepsy who continue with medical management typically only experience similar gains in QOL in the rare circumstance of spontaneous remission. However, epilepsy surgery patients are more often afforded the opportunity to wean completely off AEDs, providing further improvements in QOL for appropriately chosen candidates.

Does Successful Epilepsy Surgery Reduce Mortality Compared to Medical Management? There is little doubt that patients with epilepsy have a shortened life expectancy. Population-based studies demonstrate a two–threefold increase in death rate among patients with epilepsy, and studies of medically intractable patients report death rates five times that of the general population (Cockerell et al., 1997; Nilsson et al., 1997; Sperling et al., 1999; Trinka et al., 2013). Although there are a variety of causes of death, seizure-related death and sudden unexplained death in epilepsy account for up to two thirds of cases (Sperling et al., 1999). Few studies directly compare mortality rates of continued medical treatment to surgical therapy in refractory epilepsy. An adult cohort study compared patients who underwent surgery to patients evaluated for surgery but found not to be surgical candidates (Bell et al., 2010). Patients treated medically were 2.4 times more likely to die from all causes and 4.5 times more likely to have a seizure-related death compared to surgically treated patients. The risk of death was related to attainment of seizure freedom, as patients not seizure-free (regardless of treatment) were 4.6 times more likely to die at 1 year after study entry. Three other studies compared medical treatment to surgery. Vickrey et al. (1995) reported better survival following surgery, but the two other studies (Guldvog et al., 1991a; Stavem & Guldvog, 2005) found no significant differences compared to medical management. These discrepancies may be explained by the population under study, as Vickrey et al. (1995) used a medically treated population of surgically unsuitable patients, suggesting an inherent difference from the surgical group. Guldvog et al. (1991a) had a high number of surgical patients who were not seizure-free, suggesting that these patients may have been poor surgery candidates from the outset.

2067 Surgical versus Medical Treatment of Epilepsy Sperling et al. (1999) compared mortality in a cohort of adult patients who underwent epilepsy surgery and found that seizure freedom lowers mortality rate such that patients are indistinguishable from the general population. Unfortunately, seizure reduction alone does not reduce the death rate. The type of surgery did not influence mortality as long as seizure freedom was achieved (Sperling et al., 1999). Although there are risks to surgical therapy, mortality during epilepsy surgery is exceedingly rare (Sperling et al., 1999; McClelland et al., 2011). No studies have compared mortality in medically and surgically treated children. A population-based study of children with epilepsy followed over 40 years found death rates three times the general population, with 55% of deaths related to epilepsy (Sillanp€a€a & Shinnar, 2010). In this study, patients not in 5-year remission had the highest death rates, underscoring the impact of seizure persistence on survival, regardless of treatment type. A recent populationbased study of children with newly diagnosed epilepsy and 30 years of follow-up demonstrated mortality higher than the general population occurring significantly more in children with neurologic impairment and poorly controlled epilepsy (Nickels et al., 2012). Therefore, the comparison of mortality outcome between surgical and medical management hinges directly on the ability to achieve complete seizure freedom.

Which Treatment Arm Costs More? The economic burden of epilepsy is significant, with the costs of refractory epilepsy contributing disproportionately. Several studies estimate that the 15–25% of patients with refractory epilepsy are responsible for 50–80% of the cost of care (Begley et al., 1994, 2000). Estimating the monetary burden of epilepsy is difficult and requires capture of direct medical, nonmedical, indirect, and intangible costs. Direct medical costs are typically easier to define and include the costs of physician visits, medications, hospitalizations, diagnostic testing, and surgery. Indirect costs are more arbitrary and include losses from decreased productivity of the patient or their caregiver and premature death. The monetary value of loss of productivity is especially difficult to calculate when considering a pediatric population in which attainment of full cognitive potential may be limited by epilepsy. Additional indirect costs including dependent care, educational support, and behavioral therapies are often necessary, especially within the pediatric population. Although more difficult to estimate, indirect costs make up >75% of the total costs of care for refractory epilepsy (Murray et al., 1996; Begley et al., 2000). Intangible costs include the value of pain, suffering, and psychosocial burden of living with epilepsy, but are rarely measured given the difficulty in assigning monetary value (Begley & Beghi, 2002).

Any research on the cost-effectiveness of an epilepsy therapy must be carefully examined to understand which components of cost are analyzed, as exclusion of any one component may significantly alter the ultimate assessment. The comparison of continued medical care to surgical therapy for epilepsy is important given the high initial expenditures associated with surgery. However, comparing the cost of medicine to surgery requires a long-term perspective, as realization of monetary gain may take years. Although prospective collection of cost data would be the most ideal way to capture the true cost of refractory epilepsy, most studies rely on retrospective data review or methods of cost estimation using data from drug trials, literature review, or expert consensus. Platt and Sperling (2002) conducted a retrospective costanalysis for treatment of refractory TLE. Both direct and indirect costs of surgical therapy and continued medical care were compared. The model was based on several assumptions drawn from their own experience as well as average costs and outcomes derived from the literature. Although surgical therapy had higher initial costs, these were overcome within 10 years of surgery compared to the cost of continued medication trials. This was primarily secondary to reduced indirect costs of surgical treatment, as the increased likelihood of becoming seizure-free with surgery resulted in reduction in lost productivity. A retrospective case–control study compared the direct costs of epilepsy surgery for TLE to continued medication (Langfitt et al., 2007a). Direct costs were reduced by 32% in patients who were seizure-free 2 years after surgery primarily due to decreased seizure-related costs of AEDs and hospitalizations. Patients who were not seizure-free and those who declined surgery or who were not candidates showed no significant change in costs compared to baseline. Two studies examined the costs of pediatric epilepsy surgery compared to continued medication treatment. Keene and Ventureya (1999) used a decision analysis model based on expected seizure-free outcome of 67% following singlestage cortical resection and compared this to a 10% chance of spontaneous seizure remission in patients with refractory epilepsy continuing on medication alone. They included both direct and indirect cost estimates using local experience. Although surgical therapy was initially more expensive, costs equalized within 14 years. Indirect costs made up the majority of expense and were 50% less in the surgery group. Variations in their assumptions included reducing the surgical success rate to 45%, raising spontaneous remission rates to 25%, increasing surgical costs by 50%, and altering the expected use of AEDs after surgery, although none of these changes produced results favoring continued medication therapy over surgery. Widjaja et al. (2011) recently performed a similar decision analysis model comparing children undergoing surgical therapy for medically intractable epilepsy to a group of surgery-eligible patients who continued medical therapy. In Epilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

2068 M. S. Perry and M. Duchowny contrast to Keene and Ventureya (1999), this study included the use of invasive EEG monitoring, which adds considerable cost to epilepsy surgery. Surgery had an incremental cost-effectiveness ratio of $36,900 at 1 year compared to medical therapy, with a positive net 1-year monetary benefit. Again, the higher initial expenditure for epilepsy surgery was offset by superior efficacy for seizure freedom at 1 year. Although all of these studies appear to demonstrate the economic benefits of epilepsy surgery for intractable epilepsy, further research is needed to fully understand the long-term cost benefits and the relationship of reduced costs to other outcome measures (i.e., seizure freedom, QOL, mortality).

Conclusion Despite advances in the treatment of refractory epilepsy, the comparative impact of various treatments on outcome remains understudied and poorly understood. The only randomized controlled data that are available support the superiority of epilepsy surgery over continued medical management for adults with TLE, but this may not be fully applicable to the wide variety of refractory epilepsy phenotypes. Surgical therapy also offers distinct advantages for improvements in cognition, QOL, psychosocial function, costs, and mortality, but these hinge on the achievement of seizure freedom in the absence of unintended functional deficits. It is important to note that patients who experience seizure reduction postoperatively do not enjoy the same positive impacts of therapy. Therefore, choosing candidates with a high likelihood of a seizure-free outcome is critical. At the same time, it is recognized that medical management may result in seizure freedom in a subset of patients with apparent medically intractable epilepsy. Therefore, when the likelihood of seizure freedom is minimal or the adverse effects of surgical therapy are significant, continued medical management offers a reasonable and likely equally efficacious approach. When choosing between surgical and medical management of intractable epilepsy, it is important to look beyond the ultimate goal of seizure freedom and consider the potential impact of treatment on other domains of outcome to fully appreciate the treatment’s influence on the patients’ life. Although it is ethically challenging to design RCTs that compare surgical therapy to medical management, there are opportunities to compare surgical patients to the subset of surgically eligible patients that decline surgical therapy. The heterogeneity of refractory epilepsy will require multicenter collaboration to provide the patient numbers necessary to achieve meaningful data. Understanding the optimal treatment approach for all patients with intractable epilepsy will be important for improving outcomes in the future. Furthermore, understanding how the various domains of outcome relate to one another will likely improve medical decision-making for both patients and their providers. Epilepsia, 54(12):2060–2070, 2013 doi: 10.1111/epi.12427

Disclosure M. Scott Perry serves on speakers’ bureaus for Lundbeck Pharmaceuticals and Athena Diagnostics and has served on medical advisory boards for Lundbeck Pharmaceuticals. Michael Duchowny has received travel support from UCB Pharma and Cyberonics. 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.

References Alexandre L Jr, Walz R, Bianchin MM, Velasco TR, Terra-Bustamante VC, Wichert-Ana L, Ara" ujo D Jr, Machodo HR, Assirati JA Jr, Carlotti CG Jr, Santos AC, Serafini LN, Sakamoto AC. (2006) Seizure outcome after surgery for epilepsy due to focal cortical dysplastic lesions. Seizure 15:420–427. Baca CB, Vickrey BG, Vassar S, Hauptman JS, Dadour A, Oh T, Salamon N, Vinters HV, Sankar R, Mathern GW. (2013) Time to pediatric epilepsy surgery is related to disease severity and nonclinical factors. Neurology 80:1231–1239. Baker GA, Taylor J, Aldenkamp AP. (2011) Newly diagnosed epilepsy: cognitive outcome after 12 months. Epilepsia 52:1084–1091. Baxendale S, Heaney D, Thompson PJ, Duncan JD. (2010) Cognitive consequences of childhood-onset temporal lobe epilepsy across the adult lifespan. Neurology 75:705–711. Begley CE, Beghi E. (2002) The economic cost of epilepsy: a review of the literature. Epilepsia 43:3–9. Begley CE, Annegers JF, Lairson DR, Lairson DR, Reynolds TF, Hauser WA. (1994) Cost of epilepsy in the United States: a model based on incidence and prognosis. Epilepsia 35:1230–1243. Begley CE, Famulair M, Annegers JF, Lairson DR, Reynolds TF, Coan S, Dubinsky S, Newmark ME, Leibson C, So EL, Rocca WA. (2000) The cost of epilepsy in the United States: an estimate from population-based clinical and survey data. Epilepsia 41:342–351. Bell GS, Sinha S, de Tsi JD, Stephani C, Scott CA, Harkness WF, McElvoy AW, Peacock JL, Walker MC, Smith SJ, Duncan JS, Sander JW. (2010) Premature mortality in refractory partial epilepsy: does surgical treatment make a difference? J Neurol Neurosurg Psychiatry 81:716– 718. Benifla M, Rutka JT, Otsubo H, Lamberti-Pasculli M, Elliott I, Sell E, RamachandranNair R, Ochi A, Weiss SK, Snead OC III, Donner EJ. (2008) Long-term seizure and social outcomes following temporal lobe surgery for intractable epilepsy during childhood. Epilepsy Res 82:133– 138. Berg AT, Zelko FA, Levi SR, Testa FM. (2012) Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes. A prospective cohort study. Neurology 79:1384–1391. Bernasconi N, Natsume J, Bernasconi A. (2005) Progression in temporal lobe epilepsy. Differential atrophy is mesial temporal structures. Neurology 65:223–228. Bilginer B, Yalnizoglu D, Soylemezoglu F, Turanli G, Cila A, Topςu M, Akalan N. (2009) Surgery for epilepsy in children with dysembryoplastic neuroepithelial tumor: clinical spectrum, seizure outcome, neuroradiology, and pathology. Childs Nerv Syst 25:485–491. Chang EF, Wang DD, Barkovich AJ, Tihan T, Auguste KI, Sullivan JE, Garcia PA, Barbaro NM. (2011) Predictors of seizure freedom after surgery for malformations of cortical development. Ann Neurol 70:151–162. Chen LS, Wang N, Mei-Ing L. (2002) Seizure outcome of intractable partial epilepsy in children. Pediatr Neurol 26:282–287. Choi H, Sell RL, Lenert L, Muennig P, Goodman RR, Gilliam FG, Wong JB. (2008) Epilepsy surgery for pharmacoresistant temporal lobe epilepsy. A decision analysis. JAMA 300:2497–2505. Coan AC, Appenzeller S, Bonilha LM, Cendes F. (2009) Seizure frequency and lateralization affect progression of atrophy in temporal lobe epilepsy. Neurology 73:834–842. Cockerell OC, Johnson AL, Sander JWAS, Shorvon SD. (1997) Prognosis of epilepsy: a review and further analysis of the first nine years of the British national general practice study of epilepsy, a prospective population-based study. Epilepsia 38:31–46.

2069 Surgical versus Medical Treatment of Epilepsy Cossu M, Lo Russo G, Francione S, Mai R, Nobili L, Sartori I, Tassi L, Citterio A, Colombo N, Bramerio M, Galli C, Castana L, Cardinale F. (2008) Epilepsy surgery in children: results and predictors of outcome on seizures. Epilepsia 49:65–72. Dupont S, Tanguy ML, Clemenceau S, Adam C, Hazemann P, Baulac M. (2006) Long-term prognosis and psychosocial outcomes after surgery for MTLE. Epilepsia 47:2115–2124. Elsharkawy AE, Thorbecke R, Ebner A, May TW. (2012) Determinants of quality of life in patients with refractory focal epilepsy who were not eligible for surgery or who rejected surgery. Epilepsy Behav 24:249– 255. Engel J Jr, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, Sperling M, Gardiner I, Erba G, Fried I, Jacobs M, Vinters HV, Mintzer S, Kieburtz K. (2012) Early surgical therapy for drug-resistant temporal lobe epilepsy. JAMA 307:922–930. Freitag H, Tuxhorn I. (2005) Cognitive function in preschool children after epilepsy surgery: rationale for early intervention. Epilepsia 46:561– 567. Gilliam F. (2002) Optimizing health outcomes in active epilepsy. Neurology 58:S9–S20. Gilliam F. (2003) The impact of epilepsy of subjective health status. Curr Neurol Neurosci Rep 3:357–362. Gilliam F, Kuzniecky R, Meador K, Martin R, Sawrie S, Viikinsalo M, Morawetz Faught E. (1999) Patient-oriented outcome assessment after temporal lobectomy for refractory epilepsy. Neurology 53:687–694. Gilman J, Duchowny M, Jayakar P, Resnick T. (1994) Medical intractability in children evaluated for epilepsy surgery. Neurology 44:1341–1343. Griffiths SY, Sherman EM, Slick DJ, Eyri K, Connolly MB, Steinbok P. (2007) Postsurgical health-related quality of life (HRQOL) in children following hemispherectomy for intractable epilepsy. Epilepsia 48:564– 570. Guarnieri R, Walz R, Hallak JE, Coimbra E, de Almeida E, Cescato MP, Velasco TR, Alexandre V Jr, Terra VC, Carlotti CG Jr, Assirati JA Jr, Sakamoto AC. (2009) Do psychiatric comorbidities predict postoperative seizure outcome in temporal lobe epilepsy? Epilepsy Behav 14:529–534. Guilioni M, Rubboli G, Marucci G, Martinoni M, Volpi L, Michelucci R, Marliani AF, Bisulli F, Tinuper P, Castana L, Sartori I, Calbucci F. (2009) Seizure outcome of epilepsy surgery in focal epilepsies associated with temporomesial glioneuronal tumors: lesionectomy compared with tailored resection. J Neurosurg 111:1275–1282. Guldvog B, Løyning Y, Hauglie-Hanssen E, Flood S, Bjørnæs H. (1991a) Surgical versus medical treatment for epilepsy. I. Outcome related to survival, seizures, and neurologic deficit. Epilepsia 32:375–388. Guldvog B, Løyning Y, Hauglie-Hanssen E, Flood S, Bjørnæs H. (1991b) Surgical versus medical treatment for epilepsy. II. Outcome related to social areas. Epilepsia 32:477–486. Helmstaedter C, Kurthen M, Lux S, Reuber M, Elger CE. (2003) Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy. Ann Neurol 54:425–432. Hermann B, Seidenberg M, Bell B, Rutecki P, Sheth R, Ruggles W, Wendt G, Oleary D, Magnotta V. (2002) The neurodevelopmental impact of childhood-onset temporal lobe epilepsy on brain structure and function. Epilepsia 43:1062–1071. Hermann BP, Seidenberg M, Dow C, Jones J, Rutecki P, Bhattacharya A, Bell B. (2006) Cognitive prognosis in chronic temporal lobe epilepsy. Ann Neurol 60:80–87. Jonas R, Nguyen S, Hu B, Asarnow RF, LoPresti C, Curtiss S, de Bode S, Yudovin S, Shields WD, Vinters HV, Mathern G. (2004) Cerebral hemispherectomy: hospital course, seizure, developmental, language and motor outcomes. Neurology 62:1712–1721. Kanner AM, Byrne R, Chicarro A, Wuu J, Frey M. (2009) A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy. Neurology 72:793–799. Keene D, Ventureya ECG. (1999) Epilepsy surgery for 5- to 18-year old patients with refractory epilepsy- is it cost efficient? Childs Nerv Syst 15:52–54. Kemmotsu N, Girard HM, Bernhardt BC, Bonilha L, Lin JJ, Tecoma ES, Iragui VJ, Hagler DJ, Halgren E, McDonald CR. (2011) Comparison of white matter tracts and cortical volume in RTLE vs LTLE. Epilepsia 52:2257–2266.

Korman B, Bernal B, Duchowny M, Jayakar P, Altman N, Garaycoa G, Resnick T, Rey G. (2010) Atpical propositional language organization in prenatal and early-acquired lesions. J Child Neurol 25:985–993. Krsek P, Maton B, Jayakar P, Dean P, Korman B, Rey G, Dunoyer C, Pacheco-Jacome E, Morrison G, Ragheb J, Vinters HV, Resnick T, Duchowny M. (2009) Incomplete resection of focal cortical dysplasia is the main predictor of poor surgical outcome. Neurology 72:217–223. Kwan P, Brodie MJ. (2000) Early identification of refractory epilepsy. N Engl J Med 342:314–319. Langfitt JT, Holloway RG, McDermott MP, Messing S, Sarosky K, Berg AT, Spencer SS, Vickrey BG, Sperling MR, Bazil CW, Shinnar S. (2007a) Health care costs decline after successful epilepsy surgery. Neurology 68:1290–1298. Langfitt JT, Westerveld M, Hamberger MJ, Walczak TS, Cichetti DV, Berg AT, Vickrey BG, Barr WB, Sperling MR, Masur D, Spencer SS. (2007b) Worsening of quality of life after epilepsy surgery. Effect of seizures and memory decline. Neurology 68:1988–1994. Lettori D, Battaglia D, Sacco A, Veredice C, Chieffo D, Massimi L, Tartaglione T, Chricicozzi F, Staccoli S, Mittica A, Di Rocco C, Guzzeta F. (2008) Early hemispherectomy in catastrophic epilepsy. A cognitive and epileptic long-term follow-up. Seizure 17:49–63. Luciano AL, Shorvon SD. (2007) Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol 62:375– 381. Macrodimitris S, Sherman EMS, Forde S, Tellez-Zenteno JF, Metcalf A, Hernandez-Ronquillo L, Wiebe S, Jette N. (2011) Psychiatric outcomes of epilepsy surgery: a systemic review. Epilepsia 52:880–890. Malmgren K, Olsson I, Engman E, Flink R, Reydenhag B. (2008) Seizure outcome after resective surgery in patients with low IQ. Brain 131:535– 542. McClelland S, Guo H, Okuyemi KS. (2011) Population-based analysis of morbidity and mortality following surgery for intractable temporal lobe epilepsy in the United States. Arch Neurol 68:725–729. Mikati MA, Ataya N, Ferzil J, Kurdi R, El-Banna D, Rahi A, Shamseddine A, Sinno D, Comair Y. (2010) Quality of life after surgery for intractable partial epilepsy in children: a cohort study with controls. Epilepsy Res 90:207–213. Murray MI, Halpern MT, Leppik IE. (1996) Cost of refractory epilepsy in adults in the USA. Epilepsy Res 23:139–148. Neligan A, Bell GS, Sander JW, Shorvon SD. (2011) How refractory is refractory epilepsy? Patterns of relapse and remission in people with refractory epilepsy. Epilepsy Res 96:225–230. Nickels KC, Grossardt BR, Wirrell EC. (2012) Epilepsy-related mortality is low in children: a 30-year population-based study in Olmsted County, MN. Epilepsia 53:2164–2171. Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG. (1997) Cause-specific mortality in epilepsy: a cohort study of more than 9000 patients once hospitalized for epilepsy. Epilepsia 38:1062–1068. Paolicchi JM, Jayakar J, Dean P, Yaylali I, Morrison G, Prats A, Resnick T, Alvarez L, Duchowny M. (2000) Predictors of outcome in pediatric epilepsy surgery. Neurology 54:642–647. Perrine K, Hermann BP, Meador KJ, Vickrey BG, Cramer JA, Hays RD, Devinsky O. (1995) The relationship of neuropsychological functioning to quality of life in epilepsy. Arch Neurol 52:997–1003. Perry MS, Dunoyer C, Dean P, Bhatia S, Bavariya A, Ragheb J, Miller I, Resnick T, Jayakar P, Duchowny M. (2010) Predictors of seizure freedom after incomplete resection in children. Neurology 75:1448– 1453. Platt M, Sperling MR. (2002) A comparison of surgical and medical costs for refractory epilepsy. Epilepsia 43:25–31. Rowland NC, Englot DJ, Cage TA, Sughrue ME, Barbaro NM, Chang EF. (2012) A meta-analysis of predictors of seizure freedom in the surgical management of focal cortical dysplasia. J Neurosurg 116:1035–1041. Sabaz M, Lawson JL, Cairns DR, Duchowny MS, Resnick TR, Dean PM, Bleasel F, Bye AME. (2006) The impact of epilepsy surgery on quality of life in children. Neurology 66:557–561. Schmidt D, Stavem K. (2009) Long-term seizure outcome of surgery versus no surgery for drug-resistant partial epilepsy: a review of controlled studies. Epilepsia 50:1301–1309. Seiam AHR, Dhaliwal H, Wiebe S. (2011) Determinants of quality of life after epilepsy surgery: systematic review and evidence summary. Epilepsy Behav 21:441–445.


2070 M. S. Perry and M. Duchowny Selwa LM, Schmidt SL, Malow BA, Beydoun A. (2003) Long-term outcome of nonsurgical candidates with medically refractory localization-related epilepsy. Epilepsia 44:1568–1572. Shackleton DP, Trenite K-N, de Craen AJM, Vandenbroucke JP, Westendorp RGJ. (2003) Living with epilepsy. Long-term prognosis and psychosocial outcomes. Neurology 61:64–70. Shields D. (2000) Catastrophic epilepsy in childhood. Epilepsia 41:s2–s6. Sillanp€a€a M, Shinnar S. (2010) Long-term mortality in childhood-onset epilepsy. N Engl J Med 363:2522–2529. Sillanp€a€a M, Jalava M, Kaleva O, Shinnar S. (1998) Long-term prognosis of seizures with onset in childhood. N Engl J Med 338:1715–1722. Sillanp€a€a M, Haataja L, Shinnar S. (2004) Perceived impact of childhoodonset epilepsy on quality of life as an adult. Epilepsia 45:971–977. Skirrow C, Cross JH, Cormack F, Harkness W, Vargha-Khadem F, Baldewag T. (2011) Long-term intellectual outcome after temporal lobe surgery in childhood. Neurology 76:1330–1337. Smith ML, Elliott IM, Lach L. (2004) Cognitive, psychosocial, and family function one year after pediatric epilepsy surgery. Epilepsia 45:650–660. Smith ML, Kelly K, Kadis DS, Elliott IM, Olds J, Whiting S, Snyder T. (2011) Self-reported symptoms of psychological well-being in young adults who underwent resective epilepsy surgery in childhood. Epilepsia 52:891–899. Spencer S, Huh L. (2008) Outcomes of epilepsy surgery in adults and children. Lancet Neurol 7:525–537. Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Haut S, Langfitt JT, Walczak TS, Devinsky O. (2007) Health-related quality of life over time since respective epilepsy surgery. Ann Neurol 62:327–334. Sperling M, Feldman H, Kinman J, Liporace JD, O’Connor J. (1999) Seizure control and mortality in epilepsy. Ann Neurol 46:45–50.


Stavem K, Guldvog B. (2005) Long-term survival after epilepsy surgery compared with matched epilepsy controls and the general population. Epilepsy Res 63:67–75. Taylor J, Baker GA. (2010) Newly diagnosed epilepsy: cognitive outcomes at 5 years. Epilepsy Behav 18:387–403. Trinka E, Bauer G, Oberaigner W, Ndayisaba JP, Seppi K, Granbichler CA. (2013) Cause-specific mortality among patients with epilepsy: results from a 30-year cohort study. Epilepsia 54:495–501. Van Empelen R, Jennekens-Schinkel A, van Rijen PC, Helders PJM, van Nieuwenhuizen O. (2005) Health-related quality of life and selfperceived competence of children assessed before and up to two years after epilepsy surgery. Epilepsia 46:258–271. 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 346:1445–1449. Widjaja E, Li B, Schinkel CD, Ritchie LP, Weaver J, Snead OC III, Rutka JT, Coyte PC. (2011) Cost-effectiveness of pediatric epilepsy surgery compared to medical treatment in children with intractable epilepsy. Epilepsy Res 94:61–68. Wiebe S, Blume WT, Girvin JP, Eliasziw M. (2001) A randomized controlled trial of surgery for temporal lobe epilepsy. N Engl J Med 345:311–318. Wilson SJ, Saling MM, Kincade P, Bladin PF. (1998) Patient expectations of temporal lobe surgery. Epilepsia 39:167–174. Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. (1998) Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 44:740–748. Yang XL, Lu QC, Xu JW, Wang GS, Liu Q. (2011) Predictors of outcome in the surgical treatment for epilepsy. Chin Med J 124:4166–4171.