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
Nearly one third of patients with epilepsy become medically intractable, and the likeli-
hood 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 medi-
cal management, is not without adverse effects; to counsel patients wisely, practi-
tioners need to understand the advantages and disadvantages of both. Randomized
controlled trials in temporal lobe epilepsy reveal that epilepsy surgery achieves supe-
rior outcome compared to continued medical management. Although seizure free-
dom 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 pro-
Dr. Perry is the viders understand the patient variables that affect these outcome measures and how
Medical Director of the these measures impact each other. Because the data comparing surgical therapy ver-
EMU at Cook sus medical management for refractory epilepsy are limited, we review the available
Children’s Medical evidence comparing outcomes beyond seizure freedom including quality of life, cogni-
Center in Ft. Worth, tion, psychosocial function, mortality, and financial costs.
Texas. KEY WORDS: Quality of life, Cognition, Psychosocial function, Mortality, Costs,
Refractory epilepsy.

Up to one third of patients with epilepsy become med-
ically intractable, defined as failure of two appropriately
chosen and dosed antiepileptic drugs (AEDs), and have
minimal chances of seizure freedom on subsequent medi-
cation 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 randomized-
controlled trial (RCT) of surgical versus medical man-
agement, 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 out-
comes in addition to seizure control.
Beyond this single RCT, there is a paucity of class I out-
comes data that compares medical to surgical management.
This is not surprising, as formidable obstacles exist to such
research, including the heterogeneity of clinical presenta-
tion by age, etiology, and epilepsy type. Likewise, there are
ethical implications to delaying surgical therapy in select
populations. For example, certain pediatric epileptic en-
cephalopathies 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

relates with structural atrophy within and beyond the tempo-
ral lobe, which may have implications for outcomes if treat-
ment is overly delayed (Bernasconi et al., 2005; Coan et al.,
2009).
Despite these limitations, there is great value in com-
paring medical to surgical therapy for refractory epilepsy
and much can be gained by reviewing cohort and cross-
sectional 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 ther-
apy, 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 implica-
tions for cognitive development in childhood-onset epi-
lepsy, 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, specifi-
cally 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 man-
agement, surgical therapy, and in rare cases, comparison
between both treatment options. In the present manu-
script, 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 popula-
tions 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 addi-
tion 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,” “psycho-
social,” “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.
2061
Surgical versus Medical Treatment of Epilepsy
Seizure Control in Medically
versus Surgically Treated
Patients with Chronic Focal
Epilepsy
Although there are a variety of outcomes to consider fol-
lowing 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 sei-
zure-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 convinc-
ingly support the superiority of surgical therapy in appropri-
ately 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) per-
formed a meta-analysis of 20 such studies (19 nonrandom-
ized), of which 17 included only patients undergoing
temporal lobe procedures. Nonrandomized studies are sub-
ject 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 sur-
gery). 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 random-
ized 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 sur-
gery 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 Key findings
Seizure freedom
Wiebe et al. (2001) RCT Primarily adult At 1 year, patients free of seizures
(>16 years) impairing awareness was 58% for
surgical patients and 8% for
medical management
Engel et al. (2012) RCT Primarily adult At 2 years, 0 of 23 patients in
(>12 years) the medical group and 11
of 15 patients in the surgical
group were seizure-free
Schmidt and Meta-analysis Adult and pediatric 719 (44%) of 1,621 surgery
Stavem (2009) patients compared to 139
(12%) of 1,113 nonoperated
controls achieved seizure freedom
Medical management resulted
in seizure freedom in 12% of patients
Chen et al. (2002) Retrospective observational Pediatric No difference in seizure-free
case-control 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
Cognition
Skirrow Prospective observational Pediatric Full-scale IQ improved in patients
et al. (2011) case-control after surgery for TLE compared to controls
Realization of IQ improvements
took up to 6 years
Helmstaedter Prospective case-control Adult Both surgical and medical management
et al. (2003) 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
Smith et al. (2004) Prospective case-control Pediatric No significant improvement in cognitive
function was present 1 year post–epilepsy
surgery, regardless of seizure freedom
Psychosocial
Smith Observational case-control Pediatric Patients seizure-free after surgery were
et al. (2011) significantly less like to report symptoms
of psychological distress compared to
patients having seizures after surgery
or those treated with medication alone
Smith et al. (2004) Prospective case-control Pediatric No improvement in social, emotional,
or behavioral function was demonstrated
at 1 year post-op compared to
medical management
Guldvog et al. Retrospective case-control Adult Patients treated with surgery were more
(1991a,b) 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
Mikati et al. (2010) Prospective observational Pediatric Surgery patients and medical patients had
case-control 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

Table 1. Continued.
Authors Study design
Mortality
Bell et al. (2010) Retrospective case-control
Costs
Keene and Decision analysis
Ventureya (1999)
Widjaja et al. (2011) Decision analysis
Langfitt et al. (2007a) Prospective observational
case-control
(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 & Shor-
von, 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 trea-
ted patients experiencing a 42% greater reduction in sei-
zure frequency.
2063
Surgical versus Medical Treatment of Epilepsy
Patient population Key findings
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
Pediatric Initial costs are greater for surgical therapy
Surgery becomes more cost-effective
14 years after therapy, especially
in seizure-free patients
Pediatric Surgical treatment resulted in positive
monetary benefit compared to medical
management at 1 year post-op
Adult 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
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 out-
comes 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 preop-
erative 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 resec-
tion of the epileptogenic zone. Complete resection is the
only predictor of postoperative seizure freedom, which is
repeatedly supported in the literature regardless of histo-
pathologic 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 seizure-
Epilepsia, 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 inevi-
table, seizure freedom is unlikely.
In summary, the available evidence convincingly demon-
strates that patients with intractable focal epilepsy have a
higher likelihood of seizure freedom following an exci-
sional surgical procedure, and that surgical therapy is supe-
rior 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 cog-
nitive trajectory, the intrinsic pharmacoresistance of epi-
lepsy 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 intelli-
gence quotient (IQ) (Berg et al., 2012). The impact of phar-
macoresistance 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 vul-
nerable to repeated seizures. Anatomic studies in this clini-
cal cohort reveal progressive atrophy of both gray and white
matter structures. Atrophy correlates with duration of epi-
lepsy 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 intrac-
table childhood-onset TLE (Baxendale et al., 2010). Defi-
cits 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 phar-
macoresistance in adulthood more commonly impacts atten-
tion/processing and visual/verbal memory domains
compared to childhood seizure onset in which verbal com-
prehension 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 pro-
tect from further regression. Although both surgical and
medical treatment can achieve this goal, they both are asso-
ciated 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 non-
memory functions in a longitudinal study comparing adult
patients with intractable epilepsy who were undergoing
temporal lobectomy to patients who were managed medi-
cally. 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.

Skirrow et al. (2011) compared the long-term cognitive
follow-up of children undergoing temporal lobectomy to
patients on medical management owing to discordant pre-
surgical 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 improve-
ments. Although both cognitively impaired and high-func-
tioning children may benefit from seizure reduction after
surgery, high-functioning patients are at higher risk for post-
operative declines (Freitag & Tuxhorn, 2005). Patients
undergoing hemispherectomy for intractable childhood epi-
lepsies experience improvements in both motor and lan-
guage 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 free-
dom. However, the authors note that the duration of follow-
up 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 repre-
senting a potential advantage of surgical therapy over medi-
cal management.
Limited evidence from both controlled and uncontrolled
studies suggests that successful epilepsy surgery, defined as
complete seizure freedom, has the potential to improve cog-
nitive 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 manage-
ment 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 addi-
tional cognitive improvement. However, unsuccessful
epilepsy surgery may accelerate existing dysfunction or pro-
duce 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 ulti-
mately contribute to the measurement of QOL in patients
with epilepsy.
2065
Surgical versus Medical Treatment of Epilepsy
In a large Dutch cohort with newly diagnosed epilepsy
followed for >30 years, rates of marriage, learning achieve-
ment, 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 medica-
tion, regardless of seizure control. Lower rates of employ-
ment, 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 medi-
cation report fewer comorbid conditions and more positive
health outcomes (Shackleton et al., 2003). The effect of sei-
zure 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 man-
agement 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 com-
pared 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 determi-
nants of favorable QOL. Other adult studies have focused
primarily on preoperative versus postoperative QOL, dem-
onstrating 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 preexis-
tence 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). Postopera-
tive psychiatric disease most often improves or remains
unchanged in seizure-free patients, although worsening or
de novo psychiatric disease may occur in patients who con-
tinue to experience seizures (Macrodimitris et al., 2011).
It is not surprising that seizure outcome is the most impor-
tant 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
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M. S. Perry and M. Duchowny

QOL among patients with uncontrolled epilepsy is less clear patients more often become employed or attended school
(i.e., do daily seizures impact QOL more than weekly sei- (Benifla et al., 2008) and there are improvements in social
zures? Gilliam, 2003). Other studies found no significant competence, athletic competence, and emotional relation-
relationship between postoperative seizure outcome and ships (Van Empelen et al., 2005). As noted in adults, seizure
QOL (Dupont et al., 2006). Patients with unrealistic preop- freedom in children is also a major contributor to improved
erative expectations or postoperative functional deficits in QOL following epilepsy surgery (Sabaz et al., 2006; Beni-
addition to continued seizures may evidence a decline in fla et al., 2008).
QOL (Wilson et al., 1998; Langfitt et al., 2007b). Seizure freedom is pivotal to gains in QOL after epilepsy
QOL in patients with intractable epilepsy can also surgery in both adults and children. Patients with intractable
improve with continued medical management. Patients epilepsy who continue with medical management typically
rejected for epilepsy surgery may still experience signifi- only experience similar gains in QOL in the rare circum-
cant improvement in QOL, typically related to spontaneous stance of spontaneous remission. However, epilepsy surgery
seizure remission (Selwa et al., 2003). Granted, spontane- patients are more often afforded the opportunity to wean
ous remission occurs in only 20–30% of patients and is more completely off AEDs, providing further improvements in
commonly encountered in patients with infrequent seizures QOL for appropriately chosen candidates.
(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 affor-
Does Successful Epilepsy
ded the opportunity to become medication free (Schmidt & Surgery Reduce Mortality
Stavem, 2009; Neligan et al., 2011). Because the continued Compared to Medical
use and adverse effects of medication are also major con- Management?
tributors to QOL (Gilliam et al., 1999; Gilliam, 2002), this
There is little doubt that patients with epilepsy have a
suggests that surgical therapy resulting in seizure freedom
shortened life expectancy. Population-based studies demon-
and medication freedom will produce superior QOL out-
strate a two–threefold increase in death rate among patients
comes.
with epilepsy, and studies of medically intractable patients
Similar to the adult experience, few studies directly com-
report death rates five times that of the general population
pare the impact of surgical therapy to medical management
(Cockerell et al., 1997; Nilsson et al., 1997; Sperling et al.,
on QOL for children with intractable epilepsy. Mikati et al.
1999; Trinka et al., 2013). Although there are a variety of
(2010) compared a group of pediatric patients who under-
causes of death, seizure-related death and sudden unex-
went epilepsy surgery to controls with intractable epilepsy
plained death in epilepsy account for up to two thirds of
who were not surgery candidates and healthy individuals.
cases (Sperling et al., 1999).
Although nonsurgical patients were poor surgery candidates
Few studies directly compare mortality rates of continued
and thus not truly matched for disease state, surgery patients
medical treatment to surgical therapy in refractory epilepsy.
had better behavioral outcomes compared to nonsurgery
An adult cohort study compared patients who underwent
patients, and the QOL of patients who were rendered sei-
surgery to patients evaluated for surgery but found not to be
zure-free postoperatively were similar to healthy controls.
surgical candidates (Bell et al., 2010). Patients treated med-
Smith et al. (2011) compared psychological well-being
ically were 2.4 times more likely to die from all causes and
between seizure-free pediatric epilepsy surgery patients,
4.5 times more likely to have a seizure-related death com-
patients with postoperative seizures, and patients on medi-
pared to surgically treated patients. The risk of death was
cal therapy for intractable epilepsy. They found a modest
related to attainment of seizure freedom, as patients not
advantage in psychological well-being for seizure-free
seizure-free (regardless of treatment) were 4.6 times more
patients, but failed to demonstrate any advantage for symp-
likely to die at 1 year after study entry.
toms of depression or anxiety compared to nonsurgical
Three other studies compared medical treatment to sur-
patients. Another study comparing medical management to
gery. Vickrey et al. (1995) reported better survival follow-
epilepsy surgery in children failed to demonstrate any
ing surgery, but the two other studies (Guldvog et al.,
advantage of either therapy on behavior, emotional, or
1991a; Stavem & Guldvog, 2005) found no significant dif-
social functioning, except in cases in which epilepsy surgery
ferences compared to medical management. These discrep-
was performed at an early age (Smith et al., 2004).
ancies may be explained by the population under study, as
Improvements in QOL have been demonstrated in patients
Vickrey et al. (1995) used a medically treated population of
undergoing hemispherectomy compared to nonsurgical
surgically unsuitable patients, suggesting an inherent differ-
patients, with continued seizures and higher AED load pre-
ence from the surgical group. Guldvog et al. (1991a) had a
dicting less favorable QOL (Griffiths et al., 2007).
high number of surgical patients who were not seizure-free,
Other studies have specifically compared QOL before
suggesting that these patients may have been poor surgery
and after epilepsy surgery only (Van Empelen et al., 2005;
candidates from the outset.
Sabaz et al., 2006; Benifla et al., 2008). Postoperatively,
Epilepsia, 54(12):2060–2070, 2013
doi: 10.1111/epi.12427

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. Unfortu-
nately, 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 dur-
ing epilepsy surgery is exceedingly rare (Sperling et al.,
1999; McClelland et al., 2011).
No studies have compared mortality in medically and sur-
gically treated children. A population-based study of chil-
dren 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 sur-
vival, regardless of treatment type. A recent population-
based study of children with newly diagnosed epilepsy and
30 years of follow-up demonstrated mortality higher than
the general population occurring significantly more in chil-
dren with neurologic impairment and poorly controlled epi-
lepsy (Nickels et al., 2012). Therefore, the comparison of
mortality outcome between surgical and medical manage-
ment hinges directly on the ability to achieve complete sei-
zure 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 arbi-
trary and include losses from decreased productivity of the
patient or their caregiver and premature death. The mone-
tary 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 epi-
lepsy. Additional indirect costs including dependent care,
educational support, and behavioral therapies are often nec-
essary, 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).
2067
Surgical versus Medical Treatment of Epilepsy
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 ther-
apy for epilepsy is important given the high initial expendi-
tures 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 pro-
spective 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 estima-
tion using data from drug trials, literature review, or expert
consensus.
Platt and Sperling (2002) conducted a retrospective cost-
analysis 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 sec-
ondary 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 pri-
marily 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 sur-
gery compared to continued medication treatment. Keene
and Ventureya (1999) used a decision analysis model based
on expected seizure-free outcome of 67% following single-
stage 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 experi-
ence. Although surgical therapy was initially more expen-
sive, 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 remis-
sion 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 deci-
sion analysis model comparing children undergoing surgi-
cal 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 consider-
able 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 bene-
fit. 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 ran-
domized controlled data that are available support the supe-
riority 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 pheno-
types. 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 medi-
cal management offers a reasonable and likely equally effi-
cacious 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 multi-
center collaboration to provide the patient numbers neces-
sary 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 Pharmaceuti-
cals 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 Jour-
nal’s position on issues involved in ethical publication and affirm that this
report is consistent with those guidelines.
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