Epilepsy & Behavior 82 (2018) 179–188

Contents lists available at ScienceDirect

Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Review

Surgical versus medical treatment of drug-resistant epilepsy:

A systematic review and meta-analysis
Jin-tao Liu a,b,1, Bei Liu a,2, Hua Zhang a,⁎
a
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province,China
b
Department of Surgery, the 413th Hospital of the Chinese People's Liberation Army, Zhoushan 316000, China

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Surgery and drug therapy are the two main treatments for refractory epilepsy. However, to date, there
Received 5 April 2017 has not been an adequate comparison of the outcomes of these two treatments. This systematic review compared
Revised 2 November 2017 the overall outcome of surgery and medical treatment in patients with drug-resistant epilepsy.
Accepted 12 November 2017 Methods: Articles published in Embase, Medline, Pubmed, and the Cochrane library were searched from their
Available online 23 March 2018
inception until June 2016.
Results: Twenty of the eighty-one (24.7%) full-text articles reviewed fulfilled the eligibility criteria and were
Keywords:
Epilepsy surgery
included in the meta-analysis. Of 1800 patients with drug-resistant epilepsy, 526 of 923 patients (57.0%) in the
Cognitive function surgery group were seizure-free compared with 134 of 877 patients (15.3%) in the medical treatment group
Quality of life (19 studies, risk ratio (RR) = 3.72, 95% confidence interval (CI) [2.75–5.03]; P b 0.00001, I2 = 53%). In addition,
Antiepileptic drugs more patients were off antiepileptic drugs (AEDs) in the surgical group (3 studies, n = 438, RR = 4.76, 95% CI
Drug-resistant epilepsy [2.21, 10.28], P b 0.0001, I2 = 0%). Although different studies used different questionnaires to assess patient qual-
ity of life (QOL) in both treatment groups, the overall postintervention QOL scores were higher in the surgery
than in the medical treatment group, by SMD (6 studies, n = 459, SMD = 0.61, 95% CI [0.23, 0.98], P = 0.002,
I2 = 66%).
Conclusion: As the complications of interventions, declines in memory, and word recall/naming were not
assessed in the meta-analysis, the conclusions are limited to seizure-free, AED use, and QOL. The current evidence
indicate that compared with medical treatment, surgery is more likely to achieve seizure-free, off AEDs, and bet-
ter QOL.
© 2017 Published by Elsevier Inc.

1. Background
Epilepsy is a chronic neurologic disorder typically characterized by
recurrent and unprovoked seizures and has various clinical manifesta-
tions [1]. Globally, among the 50 million people with epilepsy, seizures
in 30% to 40% fail to respond to antiepileptic drug (AED) therapies [2,3].
Patients with drug-resistant epilepsy often experience a poor quality of
life (QOL) and a high risk of mortality, because of the increased fre-
quency of comorbidity, Sudden Unexpected Death in Epilepsy
(SUDEP), cognitive dysfunction, and alterations in psychiatric status
[4–7]. Drug-resistant epilepsy is also a social problem that produces se-
rious economic burdens. Several studies in different countries indicated
that 15% of patients with seizures that were most refractory to medical
therapy accounted for N 50% of the total costs of the illness [8–10].
⁎ Corresponding author at: Department of Neurosurgery, Tangdu Hospital, Fourth
Military Medical University, No. 569, Xinsi Road, Bridge District, Xi'an 710038, China.
E-mail address: zhanghua2016@sohu.com (H. Zhang).
1
Contributed to the main text of this work.
2
Responsible for a second review.
Surgery is one of several strategies used for the treatment of patients
with drug-resistant epilepsy [11]. In the 21st century, components of
the standard presurgical evaluation [e.g., structural magnetic resonance
imaging (MRI), SPECT, positron emission tomography (PET) and intra-
cranial electroencephalograph (EEG), and cortical stimulation] have
provided us with good cortical mapping and imaging, which improve
the safety and efficacy of surgery. Recently, more advanced techniques
[e.g., characterization of resting-state functional magnetic resonance
imaging (fMRI), connectivity, tractography, and task-specific fMRI]
promise to improve the precision and reduce the risk of surgical compli-
cations [12]. However, surgery is still associated with several adverse
events such as visual field defects, wound infections, a mild decline in
verbal memory associated with dominant resections, language decline,
ESP naming, or even some severe adverse events such as stroke,
bleeding, or death [13,14]. Nonsurgical medical treatments have also
demonstrated therapeutic efficacy. In a meta-analysis of randomized
placebo-controlled trials, newer AEDs were more effective than placebo,
though the incidence of adverse effects was higher [15].
Given that drug-resistant epilepsy (also called intractable temporal
lobe epilepsy (TLE)) represents a high proportion of the burden of epi-
lepsy, a comparison of the efficacy of surgery versus continued medical

https://doi.org/10.1016/j.yebeh.2017.11.012
1525-5050/© 2017 Published by Elsevier Inc.
180 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188
treatment is required. The results of several randomized controlled trials
(RCTs) comparing surgery with continued medical treatment for
patients with intractable TLE have suggested that the surgical outcome
is better. However, ethical issues have resulted in a paucity of higher
level evidence to support this claim [16,17]. A meta-analysis conducted
in 2009 compared surgery with nonsurgical controls and demonstrated
that the surgical treatments had advantages over nonsurgical interven-
tions [18]. However, as participants in the nonsurgical group were
treated with various conservative treatments (including pharmacologi-
cal and nonpharmacological interventions), the clinical heterogeneity
in the control group potentially influenced the estimated effect.
Furthermore, since more advanced surgery and medical treatments for
epilepsy have been developed and more trials have been published
since 2010, we have undertaken the necessary task of updating the
evidence [17,19,20].
2. Methods and material
2.1. Inclusion criteria
Study inclusion criteria were the following: (1) study design: indi-
vidual RCT and nonrandomized controlled studies; (2) patients
diagnosed with drug-resistant epilepsy, as defined in the original stud-
ies; (3) studies comparing surgery with any other type of medication for
drug-resistant epilepsy; surgery types are categorized into resective
[e.g., lesionectomy, corticectomy, lobectomy, hemispherectomy] and
nonresective procedures [e.g., multiple subpial transactions and
callosotomy]; and (4) primary outcomes include: seizure-free status:
completely seizure-free since surgery, nondisabling simple partial
seizures only since surgery, some disabling seizures after surgery but
completely seizure-free for at least 2 years, and convulsions only
when medications are withdrawn (Engel's four categories standard,
1987); secondary outcomes include: QOL, memory outcome, cognition,
and the number of patients off AEDs (We only collected data when this
outcome was observed after at least 2 years of follow-up, as very few
centers attempt to withdraw AEDs in the first 1–2 years).
2.2. Literature search
We performed a systematic search of articles published in Embase,
Medline, Pubmed, and the Cochrane library from their inception until
June 2016. There was no language limitation. We also searched bibliog-
raphies of reviews, original articles, and book chapters. The search
strategies are presented in Appendix 1.
2.3. Study selection
Two review authors (Jintao Liu and Bei Liu) independently screened
the references and full texts of potentially eligible publications. Any
disagreement was resolved by consensus.
2.4. Data extraction and management
A database for the identification and inclusion of relevant articles
was created, and the following data were extracted: i) characteristics
of the study population: the number of participants; diagnosis: spe-
cific etiologies [e.g., tumors, CNS infections], preoperative diagnosis
[e.g., electroencephalogram (EEG)/MRI, fMRI, PET], demographic
and clinical characteristics: age, sex, and length of illness; ii) charac-
teristics of the interventions: surgical management [mean or median
age at operation, side of resection, surgical procedure (resective/
nonresective), side and extent of resection], management of medica-
tion [dosage, frequency, administration], duration of treatment, and
duration of follow-up; iii) characteristics of outcomes: definition,
methods of measurement, time points of measurement, and quanti-
tative data of each outcome; and iv) information relevant to the
study design: allocation, blindness, number of participants leaving
the study early, selective reporting, funding, and other information
that may induce potential bias.
Two review authors (Jintao Liu and Bei Liu) managed the data. All
disagreements were discussed and, if conflicting views persisted, they
were resolved by a third author (Hua Zhang).
2.5. Assessment of reporting biases
For the reports not containing original data, we requested any un-
published data from the authors. We investigated reporting bias using
the Outcome Reporting Bias in Trials (ORBIT) classification system
[21]. To examine publication bias, we searched multiple sources and
contacted authors to pool all protocols. If available, we referred to the
Cochrane Handbook to create the funnel plots and judge the existence
of publication bias [22].
2.6. Data analysis and synthesis
For each category and group of interest, we measured the seizure-
related outcome after different treatments as either a good or a poor
outcome (based on Engel's four categories standard). Then, we analyzed
the result as a dichotomous outcome (seizure-free versus no seizure-
free). The definition of seizure-free was stated in inclusion criteria, we
categorized auras persisted to seizure-free. We also pooled the median
proportion of seizure-free patients and synthesized the data with a risk
ratio (RR) with 95% confidence intervals (CIs). If heterogeneity was
rated as acceptable (I2 ≤ 50%), we performed a meta-analysis using a
fixed-effects model. If heterogeneity was considered substantial and un-
explained, we performed a meta-analysis using a random-effects
model.
2.7. Assessment of heterogeneity
Differences in study design and patient characteristics were examined
to assess the heterogeneity. Statistical heterogeneity was assessed by a
chi square test (P b 0.1) coupled with the value of I2 (I2 value N 50%
rated as substantial heterogeneity). Where there was statistical heteroge-
neity, we explored the source of heterogeneity.
2.8. Subgroup analysis
A substantial amount of heterogeneity across different designs and
populations was assessed by subgroup analysis. Prognostic factors of
interest (e.g., types of surgery, PET) were also further analyzed for the
primary outcome.
3. Results
A total of 6726 records were identified through our electronic
database search, and 3 additional records were located through other
sources. Ultimately, 5309 citations were obtained after removing dupli-
cates. Eighty-one full-text articles were further assessed for eligibility.
Finally, 20 studies fulfilled the eligibility criteria and were included in
the quantitative synthesis (meta-analysis). A flow diagram depicting
the literature retrieval and trial selection is presented in Fig. 1. The
characteristics of the 20 trials are summarized in Table 1.
Of the 20 identified studies (Table 1, Supplementary Table 1), two
studies were randomized, while the others were retrospective or
prospective controlled studies. Three trials reported outcomes at
multiple time points, with a different reported outcome at each time
point. For example, one study by Stavem and Guldvog reported their
results in 1991, 2005, and 2008. Short- and long-term seizure-free
outcomes were measured, as well as a long-term QOL outcome. Eight
trials reported outcomes at multiple time points in one article. The
number of participants who were seizure-free was reported in 19 of
 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188
Fig. 1. Study selection flow diagram.
20 studies, however, one study did not report data for the medical
treatment group.
Of the 20 studies, 14 were focused on adults and 6 on children
(b18 years old). Seventeen studies were conducted in developed coun-
tries, while the other three were in developing country (Lebanon, Brazil,
China). All patients in the studies were diagnosed as drug resistant.
Seven studies defined drug-resistant epilepsy as the use of at least two
AEDs that had either not lead to freedom from seizures or had achieved
this aim at the cost of intolerable side effects. Although the other 13
studies gave no clear definition of drug resistance, the patients in
these studies were selected by healthcare professionals, and their
clinical history was consistent with the definition of refractory epilepsy.
Ten studies reported outcomes from temporal lobectomy (TL), 9 studies
from combined temporal and extratemporal lobectomy (XTL) (Table 1),
and the remaining 1 study from corpus callosotomy in children.
Characteristics of the populations at baseline including age (subgroup
in independent studies), gender, and AED were not significantly differ-
ent between the two groups. In addition, scores from different QOL and
181
memory questionnaires were obtained at baseline in studies to ensure
comparability between the surgery and medical treatment groups.
Patient characteristics in the medical treatment group were fully
described in 18 of the 20 studies (Supplementary Table 2). In 5 studies,
patients who were selected and recruited as the medical treatment
group were being evaluated for epilepsy surgery during the same
period. In thirteen studies, the medical treatment group consisted of
patients who underwent presurgical evaluation but were ineligible for
surgery and those who declined the physician's recommendation
(Supplementary Table 2).
3.1. Seizure-free
Nineteen of the twenty studies reported a seizure-free outcome. Of
1800 patients with drug-resistant epilepsy, 526 of 923 patients
(57.0%) in the surgery group were seizure-free compared with 134 of
877 patients (15.3%) in the medical treatment group. The meta-
analysis revealed that more patients were seizure-free in the surgical
182 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188

Table 1
Study characteristics.

Source Study Location Participant population Intervention Control Evaluation criterion Duration of
design group group for outcome follow-up

McLachlan (1997) PS Canada Diagnose: TLE n = 51 n = 21 No auras 1 year

Age: N17 TL Med
Sex: male = 31; female = 41
Markand (2000) PS U.S.A. Diagnose: TLE n = 53 n = 37 Engel class I 2 years
Age: Med: 15–58; Sur: 10–57 TL Med
Sex: male = 51; female = 39
Wiebe (2001) RCT Canada Diagnose: TLE n = 40 n = 40 No auras/with auras 1 year
Age: N16 TL Med
Sex: male = 38; female = 42
Chen (2002) RS U.S.A. Diagnose: TLE & XTLE n = 20 n = 30 No auras/with auras 4 years
Age: Med: 4.1 ± 0.7; Sur: 3.2 ± 0.6 TL & XTL Med
Sex: children, not stated
Kumlien (2002) RS Sweden Diagnose: TLE n = 36 n = 47 Undefined 3.8 ± 1.9 years
Age: Med: 39; Sur: 36 TL Med
Sex: male = 42; female = 41
Cunha (2003) PS Portugal Diagnose: TLE n = 19 n = 18 Undefined 6 months
Age: Med: 37.6; Sur: 33.6 TL Med
Sex: male = 21; female = 16
Helmstaedter (2003) PS German Diagnose: TLE n = 147 n = 102 Undefined 2–10 years
Age: Med: 35 ± 11; Sur: 31 ± 10 TL Med
Sex: male = 116; female = 133
Smith (2004) PS Canada Diagnose: TLE & XTLE n = 30 n = 21 Engel class I 1 year
Age: 7–18 TL & XTL Med
Sex: male = 26; female = 25
Mikati (2006) PS Lebanon Diagnose: TLE n = 20 n = 17 Engel class IA 3 years
Age: Med:31.4 ± 9.27; Sur: 30.50 ± 9.8 TL Med
Sex: male = 16; female = 21
Bien (2006) PS Germany Diagnose: TLE & XTLE n = 131 n = 49 Undefined 4–13 years
Age: Med: 36.6; Sur: 31.1 TL & XTL Med
Sex: male = 86; female = 94
Yasuda (2006) PS Brazil Diagnose: TLE n = 26 n = 75 Engel class IA 20 months
Age: Med: 39.5 ± 9.3; Sur: 36.2 ± 9.4 TL Med
Sex: male = 36; female = 65
Picot (2008) PS France Diagnose: TLE & XTLE n = 119 n = 164 Engel class I, ILAE 3 years
Age: 15–60 TL & XTL Med
Sex: male = 108; female = 175
Stavem (2008) PS Norway Diagnose: TLE & XTLE n = 139 n = 139 Undefined 15 years
Age: 4–60 TL & XTL Med
Sex: male = 176; female = 102
Widjaja (2011) RS Canada Diagnose: TLE & XTLE n = 15 n = 15 Engel class I 1 years
Age: b18 TL & XTL Med
Sex: children, not state
Engel (2012) RCT U.S.A. Diagnose: TLE n = 15 n = 23 No auras/with auras 2 years
Age: N12 TL Med
Sex: male = 18; female = 20
Jones (2013) PS U.S.A. Diagnose: TLE n = 63 n = 28 No auras 17 years
Age: N18 TL Med
Sex (follow-up): male = 41; female = 43
Liang (2014) PS China Diagnose: Lennox–Gastaut syndrome n = 23 n = 37 With or without auras 5 years
Age: 6–12 Corpus callosotomy Med
Sex: male = 38; female = 22
Vogt (2014) RS Germany Diagnose: TLE n = 11 n=8 Undefined Sur: 16 months
Age: Med:43.6 ± 11.03; Sur: 43.45 ± 11.36 TL Med Med: 80.5 months
Sex: male = 10; female = 9
Oldham (2015) RS U.S.A. Diagnose: TLE & XTLE n = 78 n = 16 ILAE class 1 1 year
Age: Med:8.7; Sur: 9.9 TL & XTL Med
Sex: male = 48; female = 46
Otsuki (2016) RS Far-East Asia Diagnose: TLE & XTLE n = 45 n = 179 ILAE class 1 3 years
Age: b6 TL & XTL Med
Sex: male = 184; female = 133

Notes:
RCT: randomized controlled trial; RS: Retrospective Study; PS: Prospective Study.
ILAE: International League Against Epilepsy.
TLE: temporal lobe epilepsy; XTLE: extratemporal lobe epilepsy.
TL: temporal lobectomy; XTL: extratemporal lobectomy.
Sur: Surgery treatment; Med: Medical treatment.

than the medical treatment group (19 studies, n = 1800, RR = 3.72, 95%
CI [2.75–5.03]; P b 0.00001). Assessment of heterogeneity by the I2
method showed moderate heterogeneity of 53% (P = 0.004) (Fig. 2).
Partial heterogeneity was present because, in six studies (Engel 2012,
Markand 2000, McLachlan 1997, Smith 2004, Wiebe 2001), none of
the patients under medical management were seizure-free, which
made the RRs from these studies significantly larger than the overall RR.
We also conducted subgroup analyses to explore the impact of po-
tential clinical or methodological variability on the estimated seizure-
free effect. We conducted an analysis of subgroups from different
 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188
Fig. 2. Forest plot of the proportion of patients who are seizure-free (surgical versus medical treatment). Notes: Individual studies are depicted with their corresponding 95% CI. I2 is a
measure of heterogeneity between the studies.
study designs (prospective versus retrospective studies), different study
populations (children versus adults), from studies that used different
techniques to locate the epilepsy foci (PET/SPECT versus no-PET/
SPECT), and different domains of resection (TL; XTL; TL and XTL; and
corpus callosotomy). The results showed that i) both prospective and
retrospective studies supported that surgery was associated with a
better seizure-free outcome than medical treatment (Supplementary
Fig. 1), ii) surgery was superior to medical treatment in obtaining a sei-
zure-free outcome in both adults and children (Supplementary Fig. 2),
iii) surgery was better than medical treatment in obtaining seizure-
free in both PET/SPECT group and no PEG/SPECT groups (Supplemen-
tary Fig. 3), and iv) TL and TL plus XTL resulted in a higher proportion
of patients that were seizure-free than medical treatments, but there
was no clear difference between corpus callosotomy and medical
treatment (Supplementary Fig. 4).
3.2. Off AED use
Eight studies reported on the discontinuation of AEDs: three studies
reported the number of patients who were off AEDs after more than
3 years of follow-up, two studies observed this outcome after less than
2 years of follow-up, two studies assessed the total dosage of AEDs,
and one study reported the number of people whose anticonvulsants
were switched or whose doses were increased (Table 2). All 8 studies
reported that more patients in the surgical group took less AEDs than
in the medical treatment group. In the 3 studies that assessed the
number of patients off AEDs, 50 of the 258 patients (19.4%) in the sur-
gery group were off AEDs compared with 7 of 180 patients (3.9%) in
the medical treatment group. Overall, more patients were off AEDs in
the surgical group (3 studies, n = 438, RR = 4.76, 95% CI [2.21, 10.28],
P b 0.0001, I2 = 0%). The assessment of heterogeneity by the I2 method
showed a statistical heterogeneity of 0% (Fig. 3).
3.3. QOL
To investigate the QOL in patients after surgery, we pooled data de-
rived from different scales used in different articles (Table 2). Thirteen
183
of the 20 articles reported the QOL, while seven studies did not. The
scales used to measure QOL varied among studies: 4 studies used the
QOLIE-89 questionnaire, 3 studies used the ESI-55 questionnaire, 2
used the QOLIE-31 questionnaire, 2 studies used the QOLIE-10 question-
naire, 1 used a 10-point scale, and 1 study reported psychiatric syn-
dromes as one part of the QOL. However, data in some studies were
incomplete (the reasons are provided in Table 2). Six of the thirteen
articles reported postintervention QOL were included in the quantita-
tive synthesis. The overall QOL scores were higher in the surgery
group than in the medical group, by SMD (6 studies, n = 459, SMD =
0.61, CI [0.23, 0.98], P = 0.002, I2 = 66%, Fig. 4a).
3.4. Cognitive function
Seven of the twenty articles compared the changes in cognitive func-
tion between the surgery and medical treatment groups. Different re-
ports used different questionnaires (Table 2), and 3 of the 7 articles
could be pooled in a meta-analysis. All resections performed in the
three studies were nondominant resections. Overall, scores were higher
in the surgery than the medical treatment group, by SMD (3 studies, n
= 301, SMD = 1.25, CI [0.66, 1.83], P b 0.001, I2 = 76%, Fig. 4b).
3.5. Memory
Seven of the 20 articles reported the difference in memory function
between the two groups. Data from the different scales are presented in
Table 2. Three of the seven articles reported a better outcome in the
surgery compared with the medical treatment group, while one study
reported the opposite (Vogt, 2014). Three studies reported different
outcomes regarding different aspects of memory functions, such as
Logical Memory Immediate, Naming and Delayed Recalls. Details are
presented in Table 2.
4. Discussion
For decades, the option of surgical treatment for patients with drug-
resistant epilepsy has been widely accepted, though there is still some
184 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188

Table 2
Description of outcomes in the included studies.

Source Secondary outcome

Off AEDs Outcome of health-related Cognitive function Memory function

quality of life (HRQOL)

McLachlan (1997) Sur better ESI-55 questionnaire ESI-55 questionnaire –

Med: 1/13; Sur: 14/40 Incomplete data (no Std) Incomplete data (no Std)
Mean: Sur better Mean: Sur better
Markand (2000) Sur better QOLIE-89 questionnaire QOLIE-89 questionnaire QOLIE-89 questionnaire
Med: 0/37; Sur: 1/57 Mean: Sur better Mean: Sur better Mean: Sur better
Wiebe (2001) Sur better QOLIE-89 questionnaire – –
People whose anticonvulsants Incomplete data (no Std)
were switched or doses were increased Mean: Sur better
Med: 40/40; Sur: 9/40
Chen (2002) – – Simple clinical measurements –
Incomplete data
Kumlien (2002) – – – –
Cunha (2003) – Symptom Checklist-90 (SCL-90) – –
Incomplete data (no Std)
Mean: Sur better
Helmstaedter Sur better QOLIE-10 questionnaire Nonmemory function Boxplot: Sur better
(2003) Med: 1/102; Sur: 13/147 9.8% of surgical and 32.6% of medically Boxplot:
treated patients had scores below the 16% No significant difference
Mean: Sur better
Smith (2004) – – Cognitive outcome Percentage of participants improved
Psychosocial findings No significant difference
Family function
No significant difference
Bien (2006) No. of AEDs ESI-55 questionnaire ESI-55 questionnaire –
Med: 2.4 ± 1.1; Sur: 1.5 ± 1.2 Mean: Sur better Mean: Sur better
Mikati (2006) – ESI-55 questionnaire ESI-55 questionnaire –
Mean: Sur better Mean: Sur better
Yasuda (2006) – – – –
Picot (2008) – QOLIE-31 questionnaire – –
SEALS questionnaire
Incomplete data
Stavem (2008) Sur better QOLIE-89 questionnaire – QOLIE-89 questionnaire
Med: 5/69; Sur: 21/69 Mean: Sur better Mean: Sur better
Widjaja (2011) – – – –
Engel (2012) – QOLIE-89 questionnaire – WMS-R22 questionnaire
O'Brien nonparametric global Logical Memory Immediate,
multivariate test Delayed Recall, Verbal recall declines
Mean: Sur better Mean: Med better
Jones (2013) Sur better A 10-point scale – –
Med: 1/9; Sur: 16/42 Mean: Sur better
Liang (2014) No significant difference QOLIE-31 questionnaire (improvement) – WCIS-CR (improvement)
No. Of AEDs Med: 2/34; Sur: 13/21 Med: 2/34; Sur: 10/23
Med: 2.52 ± 0.67; Sur: 2.76 ± 1.05 Mean: Sur better Mean: Sur better
Vogt (2014) – QOLIE-10 questionnaire – Memory performance
Mean: Med better Mean: Med better
Oldham (2015) – – – –
Otsuki (2016) – – – –

Notes
Sur: Surgery treatment; Med: Medical treatment.

hesitation because of the associated side effects [23,24]. In addition,
with the recent development of new and effective AEDs [25], medical
treatment for patients with drug-resistant epilepsy has regained
popularity. Nevertheless, evidence suggests that surgical treatment
may be more efficacious in controlling seizures in this group of patients.
A systematic review in 2009 by Schmidt and Stavem compared the sei-
zure-free outcome in patients who underwent surgery with patients
who received a nonsurgical approach that included both drug and non-
drug-related conservative treatments. The authors found that 719 of
1621 (44%) patients who underwent surgery primarily for TLE were sei-
zure-free compared with 139 of 1113 (12%) patients in the nonsurgical
control group (pooled RR 4.26, 95% CI 3.03–5.98) [18]. Similarly, we
found that more patients in the surgery group were seizure-free com-
pared with those in the medical treatment group. Of note, in our
study, the control group, which only included patients who continued
medical treatment, was more homogeneous than the nonsurgery con-
trol group in the 2009 systematic review. However, the estimated
pooled RR is similar in the two reviews, again supporting the greater ef-
ficacy of surgery in controlling seizures in patients with drug-resistant
epilepsy.
We also explored the factors that may influence the seizure-free
outcome. One such factor is the role that PET may play in determining
the treatment. Studies have shown that 18F-FDG-PET can help assess
aspects of interictal brain dysfunction, which has been demonstrated
to be particularly useful in patients with negative MRI [26,27]. A study
by Uijl et al. also suggested that the findings on a PET scan in patients
with medically refractory TLE may be sensitive enough to be used as a
basis for determining a surgical approach [28]. However, we found
that there was no difference in the incidence of seizure-free outcome
between the presurgery PET group and the group of patients who only
received an MRI, suggesting that PET may not influence the surgical
outcome. However, additional prognostic studies are required to
confirm this observation. Another factor that influences posttreatment
outcomes in adults is age at the time of surgery [29]. We also found
 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188 185

Fig. 3. Forest plot of the proportion of patients who are off AEDs (surgical versus medical treatment). Notes: Individual studies are depicted with their corresponding 95% CI. I2 is a measure
of heterogeneity between the studies.

that, when compared with children, surgery had a greater effect on the
seizure-free outcome in the adult population (RR 4.41 in adult
population versus RR 2.93 in children population). While the incidence
of seizure-free status between the two populations was similar in the
medically treated groups (81/589 in adult population and 53/288 in
children population), but was much higher for adults than children
who were surgically treated (432/712 in adults versus 94/211 in
children). This finding may provide hypothesis for further studies, but
cannot draw any conclusion. In that, this is a subgroup analysis that is
only based on one factor, the age. Other potential prognostic factors
may be imbalanced between subgroups. For instance, this greater effect
of surgery on seizure-free may not relevant to age group (adult and
children), but it may be induced by the preference of surgeries in
these two populations. As the neocortical resections being performed
more frequently in the children than in the adult group, the outcome
of neocortical resections is inferior to other resections. Subgroup
analysis also found that TL and TL plus XTL had better effect than
medical treatment for seizure-free; but no statistical difference was
found between corpus callosotomy and medical treatment. Even
though, this result cannot conclude that corpus callosotomy had similar
effect with medical treatment for seizure-free, as the estimate of effect
was very imprecise which was induced by the very low incidence of
events (3/57) and small sample size (57 participants).
A review in 2013 addressed additional outcomes beyond seizure
control such as QOL, cognition, psychosocial function, mortality, and
financial costs. The data suggested that surgical treatment offered
distinct advantages for improvements in cognition, QOL, psychosocial
function, costs, and mortality [30]. An earlier report by Téllez-Zenteno
also demonstrated that surgical treatment was associated with better
outcomes of QOL and psychosocial function. Both reviews stated that a
better or worse QOL outcome or function usually depended on whether
a particular patient had achieved a seizure-free status [30,31]. Our data
also supported improved postintervention QOL with surgical compared
with medical treatment. In terms of memory, however, the findings are
inconsistent (Table 2). Because different studies measured different
aspects of memory, the data could not be combined. In one RCT, the Log-
ical Memory Immediate and Delayed Recall scores were higher in the
medical than in the surgery group [17]. However, the results were
reversed when assessing the categories of verbal recall decline and
naming. Because of these inconsistencies, additional independent
studies are required to adequately assess how surgery affects different
aspects of memory.

Fig. 4. a Forest plot of the overall scores of quality of life (QOL): various scales (surgical versus medical treatment). b Forest plot of the scores of cognitive function: various scales (surgical
versus medical treatment). Notes: Higher score indicates better cognitive function. Individual studies are depicted with their corresponding 95% CI. I2 is a measure of heterogeneity
between the studies.
186 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188

In our study, the average rate of discontinuation of AEDs was slightly and QOL. These conclusions, however, are mostly based on low level
higher in the surgery group (19%) than the medically treated group evidence and should be used with caution by clinicians and other
(3%). This finding may be confounded by the fact that more participants healthcare providers.
in the surgery group achieved seizure-free. It's very likely for those with
seizure-free to be lack of need for AED. Our review did not collect data 5.2. Implication for research
for complications relevant to interventions, however, several recent
surgical series focusing on surgery complications are published and More RCTs are required to compare the differences between surgery
report about 4%–20% rates of minor complications, and 2%–4% rates of and medically treated patients in terms of seizure-free status, QOL, AED
major or unexpected complications [32–34]. use, and memory function. The data should be measured and reported
in a uniform way. In addition, more standard scales are needed to
4.1. Strength and limitations unify the results of different observations regarding QOL.
Supplementary data to this article can be found online at https://doi.
Specific inclusion criteria were used to select the medically treated org/10.1016/j.yebeh.2017.11.012.
to reduce the degree of heterogeneity in the control group. However,
as participants in other studies were assigned to medical treatment Acknowledgment
for different reasons (Supplementary Table 2), heterogeneity among
the population still existed, which likely increased the beneficial effect This work was supported by grants from National Natural Science
of surgery over medical treatment. Although baseline patient character- Foundation of China (81271433, 81471322, 81401069).
istics were measured in all included studies, the participants assigned to
the surgery group were also nonrandom based on different surgical Conflict of interest
indications (specific etiologies, seizure frequency, age at the onset of
seizures). The study conducted by Engel is the only recent RCT in The authors declared no conflict of interest.
10 years. Although the trial was terminated early and did not recruit a
sufficient number of patients, the highly significant findings are never- Appendix 1. Search strategies
theless remarkable. Other observational studies lacked randomization
and blindness. Therefore, these factors may all contribute to a greater A. Cochrane library
perceived benefit of surgery versus medical treatment. Another limita-
tion of our review is that we did not collect data regarding adverse #1 MeSH descriptor: [Epilepsy] explode all trees
events associated with the interventions. We intend to address the #2 MeSH descriptor: [Seizures] explode all trees
safety issues surrounding both surgery and medical treatment in future #3 (epilep* or seizure* or convuls*):ti,ab,kw (Word variations have
studies. been searched)
To address the clinical question of whether surgery or medical #4 #1 or #2 or #3
treatment is better in the treatment of drug-resistant epilepsy, we
#5 MeSH descriptor: [Neurosurgical Procedures] explode all trees
conducted comprehensive search with two independent reviewers
who extracted the relevant data. We also used a subgroup analysis to #6 (callosotomy or callosum* or hemispherectomy or resection* or
address the issue of heterogeneity among different research groups. transection* or lobectomy or lesionectomy or “Vagus nerve stim-
In this field, there are probably several RCTs whose progress has ulation”):ti,ab,kw (Word variations have been searched)
been hindered and that remain unpublished due to slow accrual of #7 “resective surger*”:ti,ab,kw (Word variations have been searched)
participants as well as issues surrounding ethics. In the analysis of #8 MeSH descriptor: [General Surgery] explode all trees
the QOL, the selected scales among studies were inconsistent. In #9 #5 or #6 or #7 or #8
addition, although some studies selected a unified scale, they reported #10 #4 and #9
data in different forms such as continuous variables, dichotomous #11 (epilep* near/4 surg*):ti,ab,kw (Word variations have been
variables, box plots, or ratios. As a result, the assessments reflected searched)
limited objectivity. Because different articles used their own evaluation
#12 ((extratemporal or temporal or TLE) near/4 surg*):ti,ab,kw (Word
system, the same problem existed with the assessment of cognitive
variations have been searched)
and memory functions. The substantial heterogeneity prevented the
data from being combined in these articles. #13 #10 or #11 or #12 limited to trials
Although the problem of heterogeneity and other limitations have
B. Embase
not been overcome in this review, the following conclusions can still
provide some insights into the selection of surgery versus medical 1 exp epilepsy
treatment for the management of epilepsy that is refractory to drug
2 exp seizure
therapy.
3 (epilep$ or seizure$ or convuls$).tw.
5. Conclusion 4 or/1-3
5 exp neurosurgery
5.1. Implication for clinical practice 6 (callosotomy or callosum$ or hemispherectomy or resection$ or
transection$ or lobectomy or lesionectomy or “Vagus nerve stimu-
When compared with medical treatment, surgery in drug-resistant lation”).tw.
patients with epilepsy is associated with 1) a much higher incidence of 7 (resective adj surger$).tw.
seizure-free status, 2) a slight reduction in the need for AEDs, and 8 exp general surgery
3) greater improvement in QOL. For patients underwent nondominant
9 or/5-8
lobectomies, surgery may lead to a greater improvement in cognitive
10 4 and 9
function than medical treatment. The long-term effect of surgical treat-
ment on memory remains uncertain. The complications of interventions, 11 (epilep$ adj4 surg$).tw.
declines in memory, and word recall/naming were not assessed in the 12 ((extratemporal or temporal or TLE) adj4 surg$).tw.
meta-analysis, so the conclusions are limited to seizure-free, AED use, 13 or/10-12
 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188 187

14 (clin$ adj2 trial).mp. #9 Search “General Surgery”[Mesh]

15 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).mp. #10 Search (#5 or #6 or #7 or #8 or #9)
16 (random$ adj5 (assign$ or allocat$)).mp. #11 Search (#4 and #10)
17 randomi$.mp. #12 Search (((epilep* surg*[Title/Abstract]) OR extratemporal surg*
18 crossover.mp. [Title/Abstract]) OR temporal surg*[Title/Abstract]) OR TLE surg*
19 exp randomized-controlled-trial #13 Search (#11or #12)
20 exp double-blind-procedure #14 Search ((randomized controlled trial[pt]) OR (controlled clinical trial
21 exp crossover-procedure [pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (drug therapy
[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT
22 exp single-blind-procedure
(animals[mh] NOT humans[mh])
23 exp randomization
#15 Search (#13 and #14)
24 or/14-23
25 13 and 24
C. Medline (via OVID) References
[1] Kurtzke JF. Epilepsy: frequency, causes and consequences. Arch Neurol 1992;49:342.
1 exp Epilepsy
[2] Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its
2 exp Seizures treatment. Epilepsy Behav 2014;37:59–70.
[3] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;
3 (epilep$ or seizure$ or convuls$).tw. 342:314–9.
4 or/1-3 [4] Gaitatzis A, Johnson AL, Chadwick DW, et al. Life expectancy in people with newly
diagnosed epilepsy. Brain 2004;127:2427–32.
5 exp Neurosurgical Procedures [5] Trinka E. Epilepsy: comorbidity in the elderly. Acta Neurol Scand 2003;108:33–6.
6 (callosotomy or callosum$ or hemispherectomy or resection$ or [6] McCagh J, Fisk JE, Baker GA. Epilepsy, psychosocial and cognitive functioning.
transection$ or lobectomy or lesionectomy or “Vagus nerve stimu- Epilepsy Res 2009;86:1–14.
[7] Spatt J, Bauer G, Baumgartner C, et al. Predictors for negative attitudes toward sub-
lation”).tw. jects with epilepsy: a representative survey in the general public in Austria. Epilepsia
7 (resective adj surger$).tw. 2005;46:736–42.
[8] Begley CE, Annegers JF, Lairson DR, et al. Cost of epilepsy in the United States: a
8 exp General Surgery model based on incidence and prognosis. Epilepsia 1994;35:1230–43.
9 or/5-8 [9] Begley CE, Beghi E. The economic cost of epilepsy: a review of the literature.
Epilepsia 2002;43:3–9.
10 4 and 9 [10] Begley CE, Famulari M, Annegers JF, et al. The cost of epilepsy in the United States: an
11 (epilep$ adj4 surg$).tw. estimate from population-based clinical and survey data. Epilepsia 2000;41:342–51.
[11] Engel Jr J. Surgery for seizures. N Engl J Med 1996;334:647–53.
12 ((extratemporal or temporal or TLE) adj4 surg$).tw. [12] Jette N, Wiebe S. Update on the surgical treatment of epilepsy. Curr Opin Neurol
13 or/10-12 2013;26:201–7.
[13] de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery,
14 exp clinical trial patterns of seizure remission, and relapse: a cohort study. Lancet 2011;378:
15 exp randomized controlled trials 1388–95.
[14] Georgiadis I, Kapsalaki EZ, Fountas KN. Temporal lobe resective surgery for medi-
16 exp double-blind method cally intractable epilepsy: a review of complications and side effects. Epilepsy Res
17 exp single-blind method Treat 2013;2013.
[15] Gao L, Xia L, Zhao FL, et al. Clinical efficacy and safety of the newer antiepileptic
18 exp cross-over studies drugs as adjunctive treatment in adults with refractory partial-onset epilepsy: a
19 randomized controlled trial.pt. meta-analysis of randomized placebo-controlled trials. Epilepsy Res 2013;103:
31–44.
20 clinical trial.pt. [16] Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for
21 controlled clinical trial.pt. temporal-lobe epilepsy. N Engl J Med 2001;345:311–8.
[17] Engel J, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant
22 (clinic$ adj2 trial).mp. temporal lobe epilepsy: a randomized trial. JAMA 2012;307:922–30.
23 (random$ adj5 control$ adj5 trial$).mp. [18] Schmidt D, Stavem K. Long-term seizure outcome of surgery versus no surgery for
drug-resistant partial epilepsy: a review of controlled studies. Epilepsia 2009;50:
24 (crossover or cross-over).mp. 1301–9.
25 ((singl$ or double$ or trebl$ or tripl$) adj (blind$ or mask$)).mp. [19] Jones JE, Blocher JB, Jackson DC. Life outcomes of anterior temporal lobectomy: serial
long-term follow-up evaluations. Neurosurgery 2013;73:1018–25.
26 randomi$.mp. [20] Fiest KM, Sajobi TT, Wiebe S. Epilepsy surgery and meaningful improvements in
27 (random$ adj5 (assign$ or allocat$ or assort$ or reciev$)).mp. quality of life: results from a randomized controlled trial. Epilepsia 2014.
[21] Kirkham JJ, Dwan KM, Altman DG, et al. The impact of outcome reporting bias in
28 or/14-27 randomised controlled trials on a cohort of systematic reviews. BMJ 2010;c365:
29 13 and 28 340.
[22] Cochrane handbook for systematic reviews of interventions version 5.1.0. [updated
D. Pubmed March 2011] , In: Higgins JPT, Green S, editors. The cochrane collaboration; 2011.
[23] Jehi LE. Prediction and prevention of verbal memory decline after temporal
#1 Search “Epilepsy”[Mesh] lobectomy. Epilepsy Curr 2014;14:19–21.
[24] Sherman E, Wiebe S, Fay-McClymont TB, et al. Neuropsychological outcomes after
#2 Search “Seizures”[Mesh] epilepsy surgery: systematic review and pooled estimates. Epilepsia 2011;52:
#3 Search ((seizure*[Title/Abstract]) OR epilep*[Title/Abstract]) OR 857–69.
[25] Helmstaedter C, Elger CE, Witt JA. The effect of quantitative and qualitative antiepi-
convuls*[Title/Abstract] leptic drug changes on cognitive recovery after epilepsy surgery. Seizure 2016;36:
#4 Search (#1 or #2 or #3) 63–9.
[26] Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and adults. Lancet Neurol
#5 Search “Neurosurgical Procedures”[Mesh] 2014;13:1114–26.
#6 Search ((((((callosotomy[Title/Abstract]) OR callosum*[Title/ [27] Suárez-Piñera M, Mestre-Fusco A, Ley M, et al. Perfusion SPECT, SISCOM and PET 18
Abstract]) OR hemispherectomy[Title/Abstract]) OR resection* F-FDG in the assessment of drug-refractory epilepsy patients candidates for epilepsy
surgery. Rev Esp Med Nucl Imagen Mol (Engl Ed) 2015;34:350–7.
[Title/Abstract]) OR transection*[Title/Abstract]) OR lobectomy [28] Uijl SG, Leijten FS, Arends JB, Parra J, van Huffelen AC, Moons KG. The added value of
[Title/Abstract]) OR lesionectomy[Title/Abstract] [18F]-fl uoro-D-deoxyglucose positron emission tomography in screening for
temporal lobe epilepsy surgery. Epilepsia 2007;48:2121–9.
#7 Search “Vagus nerve stimulation”[Title/Abstract] [29] Panigrahi M, Vooturi S, Vadapalli R, et al. Predictors of outcome of surgery in adults
#8 Search resective surger*[Title/Abstract] with mesial lesional temporal lobe epilepsy. Int J Epilepsy 2015;2:78–83.
188 J. Liu et al. / Epilepsy & Behavior 82 (2018) 179–188

[30] Perry MS, Duchowny M. Surgical versus medical treatment for refractory epilepsy:
outcomes beyond seizure control. Epilepsia 2013;54:2060–70.
[31] Téllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy
surgery: a systematic review and meta-analysis. Brain 2005;128:1188–98.
[32] Gooneratne IK, Mannan S, de Tisi J, et al. Somatic complications of epilepsy surgery
over 25 years at a single center. Epilepsy Res 2017;132:70–7.
[33] Bjellvi J, Flink R, Rydenhag B, et al. Complications of epilepsy surgery in Sweden
1996–2010: a prospective, population-based study. J Neurosurg 2015;122(3):
519–25.
[34] Tebo CC, Evins AI, Christos PJ, et al. Evolution of cranial epilepsy surgery complica-
tion rates: a 32-year systematic review and meta-analysis: a review. J Neurosurg
2014;120(6):1415–27.