ARTICULO DE LOBULO TEMPORAL
Epilepsia, 50(6):1301–1309, 2009
doi: 10.1111/j.1528-1167.2008.01997.x
CRITICAL REVIEW AND INVITED COMMENTARY
Long-term seizure outcome of surgery versus no
surgery for drug-resistant partial epilepsy: A review of
controlled studies
*Dieter Schmidt and yzKnut Stavem
*Epilepsy Research Group Berlin, Germany; yHØKH, Research Centre, Akershus University Hospital,
Lørenskog, Norway; and zFaculty of Medicine, University of Oslo, Oslo, Norway
SUMMARY
A majority of patients with formerly drug-resis-
tant temporal lobe epilepsy become seizure-free
after surgery. However, apart from one 12-month
randomized trial, it is unclear how many become
seizure-free because of surgery. To determine the
net benefit of surgery, we performed a systematic
review and meta-analysis of the published evi-
dence of how many patients in similar studies
become seizure-free without surgery. Of 155
potentially eligible articles reviewed in full text, 29
(19%) fulfilled eligibility criteria. After excluding 9
publications, 20 studies form the base of evidence.
Overall, 719 of 1,621 (44%) of patients with mostly
temporal lobe surgery were seizure-free com-
Adjunctive treatment with resective surgery and a
change of medical regimen are both standards of care for
eligible patients with chronic drug-resistant epilepsy (En-
gel et al., 2003; French et al., 2004). A meta-analysis of
surgical outcome indicates that 2 years after surgery 55%
of patients with formerly drug-resistant temporal lobe
epilepsy are completely seizure free and 68% are free of
complex partial seizures (Chapell et al., 2003). It is
unclear, however, how many patients become seizure-free
because of surgery. To determine the net-benefit of
surgery, one would need to know how many patients in
similar studies become seizure-free without surgery
(Chapell et al., 2003). However, apart from one 12-month
Accepted October 29, 2008; Early View publication February 23,
2009.
Address correspondence to Prof. Dr. Dieter Schmidt, Epilepsy
Research Group, Goethestr.5, D-14163 Berlin, Germany. E-mail:
dbschmidt@t-online.de
Wiley Periodicals, Inc.
ª 2009 International League Against Epilepsy
1301
pared to 139 of 1113 (12%) of nonoperated con-
trols [pooled random effects relative risk (RR)
4.26, 95% confidence interval (CI) 3.03–5.98]. The
pooled risk difference in favor of surgery was 42%
(95% CI 32–51%). We found no comparative out-
come data in patients with extratemporal lobe
epilepsy only. The available evidence from mostly
nonrandomized observational studies indicates
that in appropriately selected patients with drug-
resistant temporal lobe epilepsy, the combination
of surgery with medical treatment is 4 times as
likely as medical treatment alone to achieve free-
dom from seizures.
KEY WORDS: Epilepsy surgery, Long-term
outcome, Chronic epilepsy, Antiepileptic drugs,
Seizure prognosis.
randomized trial, the long-term seizure outcome of
surgery versus medical treatment in nonoperated patients
is not well known (Wiebe et al., 2001; T!llez-Zenteno
et al., 2005).
Although most studies have focused on seizure outcome
in surgical cases, a number of epilepsy centers have
reported clinical observations of seizure outcomes in sur-
gical versus nonoperated patients, including patients who
were found unsuitable for surgery (T!llez-Zenteno et al.,
2005). The strength of inference that can be derived from
these nonrandomized studies is clearly less robust than
that from the only randomized trial; however, data from
cohort studies still inform about clinical practice in many
areas, including epilepsy. Meta-analyses of observational
data have a role in medical effectiveness research, pro-
vided that the possible sources of heterogeneity between
studies and the influence of biases or confounding factors
are carefully examined (Egger et al., 1998). Furthermore,
the question of long-term outcome may not be amenable
to randomized trials because of feasibility and ethical
1302
D. Schmidt and K. Stavem
issues. In addition, a comparison of surgical outcome
versus a change in medical regimen has become clinically
important, because recent outcome data in apparently
drug-resistant epilepsy, including in nonsurgical candi-
dates, suggest that up to 21% of patients may be rendered
seizure-free for more than 2 years by a change in regimen
(Selwa et al., 2003). Given that epilepsy is drug-resistant
in as many as one in three newly diagnosed patients
(Kwan & Brodie, 2000; Schmidt & Lçscher, 2005), uncer-
tainty about the comparative efficacy of surgery versus a
change of medical regimen in nonoperated patients, the
two commonly used treatments for chronic epilepsy, is a
strategic problem. This scenario prompted us to examine
the evidence for long-term seizure freedom following sur-
gery and after drug treatment in nonoperated patients.
Methods
Data sources
A medical librarian performed a comprehensive litera-
ture search of the PubMed, Medline, Embase, Index
Medicus, and Cochrane databases (search strategy in
Appendix). Literature searches were restricted to full-
length articles published between January 1947 and June
2007 in English, German, or French. In addition, we also
hand-searched bibliographies of reviews, original articles,
and book chapters, and consulted experts about other
studies.
Study selection and classification
Two reviewers independently applied the following
study inclusion criteria: reports of ‡20 patients of any age
undergoing resective epilepsy surgery utilizing a control
group, outcomes reported after a mean/median follow-up
of ‡1 year after surgery or initial evaluation, quantitative
report of seizure freedom with or without concurrent
antiepileptic drug (AED) treatment, and description of type
of surgery and number of patients undergoing each inter-
vention. We further classified studies by surgical topogra-
phy into those studies reporting outcomes of temporal lobe
surgery, and those grouping temporal and extratemporal
surgery together. We found a total of 31 publications and
excluded 11 articles. The remaining 20 publications form
the base of evidence for this review (see results).
Data gathering
Two reviewers independently abstracted all data,
resolving disagreements through discussion. We accepted
outcome definition as used by authors in each study. These
usually referred to seizure outcome in terms of seizure
freedom.
Data analysis
For comparison of seizure-free outcome between
surgical versus nonsurgical groups, we produced summary
Epilepsia, 50(6):1301–1309, 2009
doi: 10.1111/j.1528-1167.2008.01997.x
estimates for the studies, presenting the RR and its 95%
CI, with values >1 favoring surgery. We aggregated the
RRs in tables and a forest plot. The analysis was stratified
different ways according to subgroups as a sensitivity
analysis, because of heterogeneity between studies. We
had considered assessing the influence of different vari-
ables in a meta-regression analysis, but we realized that
the limited number of studies, the heterogeneity between
the studies, and association between various variables
would raise a number of problems that could not be
resolved. Therefore, we have abstained from presenting a
meta-regression and instead presented RRs for a number
of subgroups. Two studies reported more than one follow-
up period (McLachlan et al., 1997; Picot et al., 2008), and
one had separate reports for different time intervals (Sta-
vem & Guldvog, 2005; Stavem et al., 2008). For these
studies, we assessed each follow-up period separately.
Hence, in one comparison, we included studies with sev-
eral follow-up periods in the same population, presenting
results for £24 months and >24 months. In the remaining
analyses, we included only results from the longest fol-
low-up time for each study, presenting results according
to length of follow-up (£24 months and >24 months),
publications with and without zero seizure-free outcome
in the medical control group, year of publication (1947–
1999 and 2000–2007), surgical topography: temporal lobe
versus temporal lobe plus extratemporal lobe, and study
design. Because of lack of information, we could not per-
form a subgroup analysis for duration of treatment prior to
surgery; definition of seizure-freedom; age at surgery; eti-
ology, mesial temporal sclerosis versus other etiology;
and choice of nonoperated group, patients on waiting lists
for surgery versus those found ineligible for surgery. We
also summarized the RRs of being without AEDs after
surgery compared to no surgery at the longest follow-up
in the studies (n = 4) that reported this, using a similar
meta-analytic technique.
The meta-analyses were done using random effects
models, aggregating studies with a weighting equal to the
inverse of the variance of the estimate for the study. Ran-
dom effects models were chosen because of heterogeneity
between studies, although fixed effects models would
have yielded essentially similar results. The weights are
not shown on the forest plots or in the tables. We assessed
interstudy variability (heterogeneity) by describing I2, that
is, the percentage of total variation across studies that is
caused by heterogeneity rather than chance (Higgins et al.,
2003). A percentage of 25%, 50%, and 75% has been sug-
gested to indicate low, medium, and high heterogeneity
(Higgins et al., 2003). In addition we present the results of
a test for heterogeneity using DerSimonian and Laird’s Q
(DerSimonian & Laird, 1986). Because of heterogeneity
between studies, we present results for subgroups rather
than for the aggregate of all studies. For seizure outcome
analysis of surgery and medical treatment, we

used seizure-free versus not seizure-free, based on the
classifications used in the included papers. The authors of
the papers used Engel’s outcome classification (Engel
et al., 2003), modifications of this, or their own outcome
classifications. The overall results are also presented using
a similar metaanalysis with risk differences as outcome.
We used the Metan procedure in Stata version 10 for all
analyses (Stata Corp., College Station, TX, U.S.A.).
Results
Evidence base
The literature search yielded 155 references, of which
31 (20%) were potentially eligible and were reviewed
independently by two reviewers. Twenty (13%) fulfilled
the eligibility criteria and constitute this analysis’ data set
(Fig. 1).
Figure 1.
Search strategy and evidence base. *Reasons for
exclusion were: duplicate publications, that is, studies
sharing the same or overlapping patient populations at
a similar follow-up period (Bien et al., 2001;
Helmstaedter et al., 2003, overlapping with Bien et al.,
2006; Haglung & Moretti Ojemann, 1993, overlapping
with Moretti Ojemann & Jung, 2006; Guldvog et al.,
1994; Stavem & Guldvog, 2005, overlapping with
Stavem et al., 2008; Mikati et al., 2004; had overlapping
populations with Mikati et al., 2006; Picot et al., 2004
had overlapping populations with Picot et al., 2008; no
quantitative seizure outcome data for the nonoperated
group F: Rausch & Crandall, 1982; Baxendale &
Thompson, 1996; Kellett et al., 1997; follow-up of less
than 1 year E: (Aydemir et al., 2004).
Epilepsia ILAE
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Epilepsy Surgery versus No Surgery
Study population and trial design
We identified 20 controlled studies (Table 1).
Except for one (Wiebe et al., 2001), all studies were
nonrandomized (Table 1). Two studies reported more
than one follow-up period (McLachlan et al., 1997;
Picot et al., 2008), and one had separate reports for
different time intervals (Stavem & Guldvog, 2005;
Stavem et al., 2008). The outcome of temporal lobe
surgery only was assessed in 17 of 20 studies, the
other three studies reported combined outcome of
temporal and extratemporal lobe epilepsy (Table 1).
We found no studies on seizure outcome for
extratemporal lobe surgery only versus AED treatment
without surgery.
In 16 of the 20 studies, controls were patients evaluated
for surgery but who did not undergo resective surgery,
three studies did not describe surgical eligibility of their
control group, and in one study patients were randomized
as controls before surgical eligibility was assessed
(Table 2). Participants in the medical control group who
were evaluated for surgery either failed to meet criteria for
surgery, declined surgery, or were waiting for surgery and
continued to receive AED treatment (Table 2). In three
early studies, controls were patients treated with AEDs
undergoing craniotomy without excision of brain tissue
(Penfield & Steelman, 1947; Penfield & Paine, 1955;
Ommaya, 1963).
Definitions of seizure-freedom in the surgical studies
fell into four main categories. In most studies (8 of 20
studies, 40%) the measure for seizure freedom was unde-
fined. In 5 of 20 studies (25%), Engel’s classification was
used (Engel et al., 1993), 1 study used in addition the
ILAE classification (Wieser et al., 2001); in 3 of 20 stud-
ies, patients were free of any seizures and auras, whereas
in a further four studies, patients having auras were con-
sidered to be seizure-free (Table 1).
The definition of seizure-freedom for surgical and
nonsurgical treatment outcome is given in Table 1.
Ninety percent of the studies focused on seizure free-
dom at the last follow-up or the last year, 5% did
not specify a time frame, and 5% offered no defini-
tion. In 90% of the studies, seizure-free outcome was
determined after the first surgery; in two studies 5%
of patients in each study underwent a second surgical
procedure (Vickrey et al., 1995; Bien et al., 2006). In
20% of studies, a change in AEDs was reported after
surgery (Penfield & Steelman, 1947; Vickrey et al.,
1995; Wiebe et al., 2001; Yasuda et al., 2006).
Although the total number of AEDs was lower in the
surgical group, a dose increase of AEDs was reported
in two studies (Wiebe et al., 2001; Yasuda et al.,
2006). In one study, surgically treated patients who
became seizure-free after surgery after a change of
medical regimen, including a modern AED, were
excluded (Kumlien et al., 2002).
Epilepsia, 50(6):1301–1309, 2009
doi: 10.1111/j.1528-1167.2008.01997.x
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D. Schmidt and K. Stavem

Table 1. Study population and trial design in 20 controlled studies comparing seizure-free
outcome in operated patients and nonoperated controls. The number of surgical patients and
controls is given in Figure 2
Seizure-free Seizure-free
outcome outcome
Study measures Type of Follow-up measures Seizure-free
Authors (year) design (surgical) surgery (years) (nonsurgical) (nonsurgical)
McLachlan et al. (1997) C/CR No auras TL 1, 2 Undefined No
Gilliam et al. (1999) C/CR No auras, with auras TL 2 No auras, with auras No
O’Donoghue et al. (1998) C/CR Undefined TL 2 Undefined Yes
Altshuler et al. (1999) C With auras TL 4–13 With auras Yes
Ommaya (1963) C/CR No aura TL 4–13 No auras No
Penfield and Steelman (1947) C Undefined TL 4–13 Undefined No
Penfield and Paine (1955) C/CR Undefined TL 4–13 Undefined No
Vickrey et al. (1995) C/CR No auras, with auras TL + XTL 4–13 No auras, with auras Yes
Markand et al. (2000) C Engel class I, no auras TL 1 No auras No
Wiebe et al. (2001) RCT No auras, with auras TL 1 No auras, with auras Yes
Yasuda et al. (2006)a C Engel class IA TL 1 Engel class IA Yes
Mikati et al. (2006) C Engel class IA TL 2 Engel class IA Yes
Bien et al. (2006) C/CR Undefined TL 4–13 Undefined Yes
Derry et al. (2001) C Undefined TL 4–13 Undefined Yes
Jones et al. (2002) C No auras TL 4–13 No auras Yes
Kumlien et al. (2002) C Undefined TL 4–13 Undefined Yes
Li (2002) C/CR Undefined TL 4–13 Undefined No
Moretti Ojemann and Jung (2006) C Author specific TL 4–13 with auras Yes
Stavem et al. (2008) C/CR Undefined TL + XTL 4–13 Undefined Yes
Picot et al. (2008) C Engel I, ILAE TL + XTL 1, 2, 4–13 Engel I, ILAE Yes
a
Additional data supplied by study author on request.
C, cohort; CR, cross-sectional; ILAE, ILAE, International League Against Epilepsy; RCT, randomized controlled trial; TL, outcome
for temporal lobe surgery only; TL + XTL, combined outcome after temporal and extratemporal lobe surgery.

Seizure-free outcome in studies comparing surgical
versus drug treatment
The weighted pooled proportion of long-term sei-
zure-free patients was determined in a total of 20
studies comparing surgical versus medical outcome
(Fig. 2). Overall, 719 of 1,621 patients (44%) with
mostly temporal lobe surgery were seizure free com-
pared to 139 of 1,113 (12%) of nonoperated controls
(RR 4.26, 95% CI 3.03–5.98). The risk difference
between surgery and medical treatment without sur-
gery was 42% (95% CI 32–51%) in favor of surgery.
Assessment of heterogeneity by the I2 method showed
moderate heterogeneity of 60% (Fig. 2), and Q was
47.05 (p < 0.001).
In four studies that reported how many patients
were off AEDs at the end of follow-up, more patients
were off AEDs in the surgical group versus the non-
surgical group; 32% vs. 6%, with an estimated
pooled RR for being off AEDs with surgery of 4.67
(95% CI 2.18–10.01) compared to medical treatment
only (McLachlan et al., 1997; Altshuler et al., 1999;
Derry et al., 2001; Stavem et al., 2008). Here, hetero-
geneity between studies was low with I2 of 0% and
Q of 0.40 (p = 0.94).
Factors that may influence seizure-free outcome
In a sensitivity analysis, we explored the impact of
potential explanatory factors for seizure-free outcome
of surgical versus medical studies in the study design
and the study population (Table 3). The heterogeneity
could also be reduced in some of the subgroups. For
assessment of outcome in different study designs we
included: duration of follow-up, random controlled
trial (RCT) versus cohort or cohort/cross-sectional,
and the effect of excluding seven medical studies
with zero seizure-free outcome (Table 3). For assess-
ment of outcome in a different study population we
included: temporal lobe surgery versus studies report-
ing a grouped outcome of temporal plus extratempo-
ral lobe surgery, studies of surgery published before
1999 (Table 3). In all subgroups surgery had a statis-
tically better outcome than continued medical treat-
ment. None of the examined factors seemed to have
a great influence of the seizure-free outcome of surgi-
cal versus no surgical treatment (Table 3). We did
not find sufficient data to explore other potential
factors such as age, reasons for patients not to have
surgery, specific etiologies, or different definitions of
seizure-free outcome.

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Epilepsy Surgery versus No Surgery

Table 2. Description of medical controls in the included studies. Participants in the medical
control group who were evaluated for surgery either failed to meet criteria for surgery (U),
declined surgery (R), or were waiting for surgery (W) and continued to receive antiepileptic drug
(AED) treatment. In three early studies, controls were patients undergoing craniotomy without
excision of brain tissue (S), and in three studies surgical eligibility of controls was not described (N).
The number of control patients for each study is given in Figure 2
Authors (year) Description of controls
McLachlan et al. (1997) Patients evaluated for surgery, but not operated on for various reasons (R, U)
Gilliam et al. (1999) Patients on waiting list after being evaluated and selected for surgery with anterior temporal lobectomy
in 1995 and 1996 (W)
O’Donoghue et al. (1998) Patients with definite epilepsy seen consecutively in an epilepsy clinic with a follow-up of 1 year. A total of
374 patients from 183 consecutive with definite epilepsy at an epilepsy follow-up clinic with ‡1 year follow-up,
and 191 consecutive patients referred for video-EEG telemetry for assessment of epilepsy surgery
(excl. those with IQ < 70). Surgical ineligibility of controls was not described (N)
Altshuler et al. (1999) Patients undergoing presurgical evaluation, who did not have surgery for lack of localized seizure focus
(12 of 13) or extratemporal focus not suitable for anterior temporal lobe resection (1 of 13) (U)
Ommaya (1963) Patients with a diagnosis of temporal lobe epilepsy presenting for surgery, were evaluated and underwent
craniotomy, but no removal of brain tissue because of ‘‘lacking focal activity’’ (U, S)
Penfield and Steelman (1947) Patients operated on 1939–1944 with craniotomy and cortical excision—treatment group (n = 59) versus
craniotomy without cortical excision (controls) (n = 16) (U, S)
Penfield and Paine (1955) Patients with negative explorations operated on between 1945 and 1950, versus surgery patients (U, S)
Vickrey et al. (1995) Patients were evaluated for surgery, but not operated on; no identified focus in 42 (91%), two contraindications
for surgery, two withdrew from surgery or evaluation (R, U)
Markand et al. (2000) Patients evaluated for surgery who were considered unsuitable for anterior temporal lobe resections or
elected against surgery (R, U)
Wiebe et al. (2001) Patients were randomized to a delay of presurgical evaluation for 1 year or surgery (W)
Yasuda et al. (2006)a Medically treated patients with mesial temporal lobe epilepsy followed for more than 12 months (personal
communication by the study author), waiting for finishing presurgical evaluation, waiting for surgery after
evaluation, or those unsuitable for surgery versus patients undergoing temporal lobe surgery (W, U)
Mikati et al. (2006) Individually matched patients undergoing presurgical evaluation, who were not eligible for surgery (no single
seizure focus, or unacceptable neurologic risk) versus consecutive patients undergoing surgery
(75% temporal lobe resections) (U)
Bien et al. (2006) Patients not eligible for surgery after presurgical assessment (focus not identified, multiple foci, unacceptable
neurologic risk) versus surgical patients (W, U)
Derry et al. (2001) Evaluated but ineligible patients receiving medical management followed for 8.5 years versus surgical patients (U)
Jones et al. (2002) Individuals who were evaluated for surgery but did not proceed to surgery and were receiving AED
treatment versus surgical patients (U)
Kumlien et al. (2002) Medically treated patients with MRI-verified mesial temporal sclerosis (excluding dual pathology, nonepileptic
seizures, nonadherence, uncertain EEG findings) who were considered unsuitable for surgery
(no reasons given) versus surgical patients (U)
Li (2002) Patients evaluated as surgical candidates who declined surgery or were found otherwise unsuitable for
surgery versus surgical patients (U)
Moretti Ojemann and Controls were patients with refractory epilepsy who were given medical treatment. Surgical ineligibility of
Jung (2006) controls not described (N)
Stavem et al. (2008) Patients operated on between 1948 and 1992 with individually matched nonoperated controls hospitalized
for severe epilepsy. Matched for age, sex, and seizure type. Surgical ineligibility of controls not described (N)
Picot et al. (2008) Controls were patients with refractory epilepsy who were given medical treatment. Following presurgical
exploration, 44% of controls were ineligible for surgery (U)
a
Additional data supplied by study author on request.

95% CI 3.03–5.98), or a pooled risk difference of 42%

Discussion
The three main results of our review of seizure-free out-
come in a total of 2,734 patients with drug-resistant
epilepsy after temporal lobe surgery versus medical treat-
ment in broadly similar nonoperated patients are first, that
on average, 719 of 1,621 (44%) of patients with mostly
temporal lobe surgery were seizure free compared to 139
of 1,113 (12%) of nonoperated controls (pooled RR 4.26,
(95% CI 32–51%), underscoring that the combination of
surgery with medical treatment is more efficacious than
medical treatment alone, confirming the result of the only
randomized study in the literature (Wiebe et al., 2001). In
addition, in the small number of studies reporting AED-
free outcome, more than four times more surgical patients
were able to discontinue AEDs compared to nonsurgi-
cal controls RR 4.67 (95% CI 2.18–10.01). Second,

Epilepsia, 50(6):1301–1309, 2009

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D. Schmidt and K. Stavem

Figure 2.
Forest plot of the proportion of patients who are seizure-free after surgical treatment and of nonoperated controls.
Event = seizure-free patients. Seizure freedom is shown as defined by study authors. AEDs may have been
discontinued in either group. The black marker and the horizontal lines show the relative risk (RR) and 95%
confidence interval (CI) for each trial. The size of the shaded square is proportional to the weight of the study (%
weight) in the pooled estimated RR. The diamond represents the pooled RR and 95% CI, using a random effects
model. I2 is a measure of heterogeneity between the studies (see Methods).
Epilepsia ILAE

nevertheless, it is remarkable that seizure-free outcome
was observed in 12% of similar patients without surgery
by AED treatment alone. This shows that drug resistance
can be overcome by medical treatment in a minority of
patients after having experienced lack of seizure control
for many years. Third, no evidence is available for seizure-
free outcome of extratemporal surgery versus no surgery.
The surgical outcome studies that were included in
our analysis (n = 20) had median 56% (range 7–85%)
seizure-free patients by authors’ definition, which is simi-
lar to the outcome of the only randomized trial where it
was reported that among the 40 surgery patients 38% were
completely free of seizures and 58% were free of seizures
impairing awareness (Wiebe et al., 2001). We found two
reviews in the literature covering a small number of
studies on seizure outcome of surgical versus medical
treatment (Cucherat, 2004; Tellez-Zenteno et al., 2007).
In one review covering five studies, improvement was
noted in surgical patients compared with controls without
providing quantitative outcome data (Tellez-Zenteno
et al., 2007). An earlier review by Cucherat (2004) cov-
ered four studies, including three studies reviewed by
Tellez-Zenteno et al. (2007) and the only randomized
controlled trial by Wiebe et al. (2001). Cucherat (2004)
concluded that the evidence was very limited, except for
the trial of Wiebe et al. (2001). The long-term seizure-free
outcome of nonsurgical patients with chronic drug-
resistant epilepsy in our review of median 5% (range
0–35%) of the studies (n = 20) is similar to that observed
for older AEDs in nonsurgical patients in other series,
which, however, provided no data for surgical patients
(14%, Bauer & Burr, 2001; 0%, Huttenlocher & Hapke,

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Epilepsy Surgery versus No Surgery

Table 3. Sensitivity analyses with different cross-classifications of studies, showing pooled relative
risks (RRs) of seizure-freedom of surgery versus medical treatment without surgery according to
individual study features. The RRs, which were determined from random effect models are similar
and their 95% confidence intervals (CIs), are overlapping. The table also shows the number of
events (=seizure-free patients) and an index of heterogeneity (see footnote)
No. of Relative risk Events Events
Study feature studies (95% CI) treatment control I2, %d p-Valuee
Follow-up duration, all papers, longest follow-up of
each studya
24 months or less 7 6.90 (2.73, 17.46) 233/421 74/592 80 <0.001
More than 24 months 13 3.82 (2.67, 5.47) 486/1200 65/521 44 0.04
Seizure-free controls onlyb, and longest follow-up 13 3.50 (2.65, 4.63) 494/955 139/916 49 0.02
of each studyb
24 months or less 4 3.44 (2.11, 5.63) 103/203 74/475 47 0.13
More than 24 months 9 3.60 (2.48, 5,22) 391/752 65/441 54 0.03
Follow-up, seizure-free controls only, all papers,
allowing for more than one follow-up period for
each paperc
24 months or less 6 4.09 (2.76, 6.06) 250/431 104/695 60 0.03
More than 24 months 9 3.60 (2.48, 5.22) 391/752 65/441 54 0.03
Year of publication, longest follow-up of each studya
1947–1999 8 4.71 (2.14, 10.38) 332/966 69/572 61 0.01
2000–2008 12 4.39 (2.89, 6.67) 387/655 70/541 62 0.002
Surgical topography, longest follow-up of each studya
Temporal lobe 17 4.77 (3.05, 7.46) 561/1268 107/894 65 <0.001
Temporal and extratemporal lobe combined 3 3.81 (2.31, 6.30) 158/353 32/219 46 0.16
Study design, longest follow-up of each studya
Cohort/randomized controlled trial 11 4.73 (3.05, 7.32) 320/540 49/427 52 0.02
Cohort/cross-section 9 3.71 (2.16, 6.37) 399/1081 90/686 61 0.008
a
Only including the longest follow-up period reported in each study population.
b
Excluding studies with no seizure-free patients in the control group.
c
Two papers presented results for more than one follow-up period.
d
Proportion of the total variance due to between study variance (I2, see Methods).
e
Der Simonian and Laird Q statistic (see Methods).

1990; 10%, Harbord & Manson, 1987). More recently, it
was shown that a significant minority of patients (16.6%)
were rendered seizure-free by addition of newly adminis-
tered AEDs, even after failure of two to five past antiepi-
leptic drugs (Schiller & Najjar, 2008). In a clinical
observation of 155 nonsurgical adult patients with chronic
epilepsy that had been resistant to previous drug therapy,
16% of all drug introductions resulted in seizure freedom
(defined as seizure freedom at last follow-up for
12 months or longer), and 28% of the patients were
rendered seizure free by a drug introduction (Luciano &
Shorvon, 2007).
Although our large review summarizes the available
literature on seizure-free outcome in a total of more than
2,700 patients with drug-resistant epilepsy undergoing
surgery versus no surgery, it has a number of limitations.
One of the important limitations of most studies in our
review is the lack of randomization and the inherent bias
in the selection of control groups, which because of the
nature of the surgery may not be entirely comparable to
the surgical patients, since there was always a reason that
they did not proceed to surgery. However, the predomi-
nant abnormalities were in the temporal lobe in the medi-
cally treated control subjects and in the surgical group.
Our data present the best available evidence for long-
term outcome (in the absence of long-term randomized
trials), and are informative on the outcome of two stan-
dard strategies for treating patients with drug-resistant
partial epilepsy. Except for one 12-month randomized
trial, outcome following surgery versus no surgery was
determined in nonrandomized cohort and cohort/cross-
sectional studies. The cross-sectional design may be a
limitation because it does not control for potential con-
founders associated with surgical intervention (e.g., pla-
cebo effect), selection bias, or the possible improvement
of a nonsurgical control over time when treated in a com-
prehensive epilepsy center. Alternative study designs
using prospective, nonrandomized medical controls or
presurgical assessments as controls, however, do not
eliminate selection bias or confounding effects poten-
tially associated with surgery. An early study, at a time
when medical options were limited, attempted to assess
the potential placebo effect of surgery. Although the
inclusion of studies as far back as 1947 has obvious

Epilepsia, 50(6):1301–1309, 2009

doi: 10.1111/j.1528-1167.2008.01997.x
1308
D. Schmidt and K. Stavem
limitations, the comparison of nonresection surgery and
completeness by showing all available studies speak in
favor of including early studies. In addition, according to
the sensitivity analysis, shown in Table 3, publication
data of the study did not appear to influence outcome.
The Penfield surgical series from 1947 demonstrated that
5 of 16 patients (32%) of a ‘‘sham’’ control group who
received an exploratory craniotomy without cerebral
resection experienced a 50% or higher seizure reduction,
but none became seizure-free (Penfield & Steelman,
1947). The series by Ommaya also explored a nonsurgi-
cal control group of 25 patients undergoing craniotomy
without cerebral resection (Ommaya, 1963). Again, none
of the controls became seizure free (Ommaya, 1963).
The series from the Bonn University compared seizure-
free outcome in three nonsurgical control groups and
found clinically important differences in seizure-free out-
come (Bien et al., 2006). Patients who were unsuitable
for surgery had the highest seizure-free rate of 24%,
whereas patients awaiting presurgical assessment or
withdrawing from waiting for presurgical assessment had
much lower rates of 5% and 14%, respectively (Bien
et al., 2006). This study shows that the choice of nonsur-
gical controls can influence the seizure outcome. In addi-
tion, not all patients in the medical and the surgical group
were treated with AEDs over the years in the epilepsy
center doing surgery; many were treated elsewhere
(Moretti Ojemann & Jung, 2006). In addition, we found
heterogeneity within surgical and within nonsurgical
studies in terms of follow-up including outcome mea-
sures used to determine seizure-freedom, reasons for con-
trols not to have surgery, and attrition of patients during
long-term follow-up. Furthermore, there was insufficient
information to assess the outcome on an intent-treat
basis, which would have been desirable given the attri-
tion rate during long-term observations. Also, we could
not perform a formal assessment or a ranking of the qual-
ity of the studies, and some studies had a difference in
follow-up between the surgical and the nonsurgical arms.
Finally, there may have been a publication bias, as some
of the small studies may not have been published.
Although it is important to point out this heterogeneity,
we suggest that a comparison of summary outcome of
surgery versus nonsurgical treatment may be useful for
guidance and long-term evaluation of the net benefit of
surgery that has not been evaluated in a large review.
Finally, we have not included complications of surgery
and of AED treatment or effects of withdrawal of AEDs
in patients seizure-free after surgery (Schmidt et al.,
2004) in this review, so we cannot provide a long-term
risk-benefit analysis of surgery versus drug therapy.
The main implications of our results are the following.
(1) Surgery is four times as likely as medical treatment
alone to transform drug resistance into full drug response
resulting in seizure-free outcome. The difference in effect
Epilepsia, 50(6):1301–1309, 2009
doi: 10.1111/j.1528-1167.2008.01997.x
between pooled RR was 42% in favor of surgery. (2)
Nevertheless, it is remarkable that seizure-free outcome
was observed in 12% of nonsurgical patients by AED
treatment alone. This suggests that drug resistance can be
overcome by medical treatment in a minority of patients
after having experienced lack of seizure control for many
years. (3) An important minority of seizure-free surgical
patients (but only very few nonsurgical cases) are able to
discontinue AEDs.
Acknowledgment
We confirm that we have read the Journal’s position on issues
involved in ethical publication and affirm that this report is consistent
with those guidelines.
Disclosure: We have no conflict of interest.
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Appendix
Literature search strategy
1. First step
‘‘Epilepsy/surgery’’ [MeSH] OR (‘‘epilepsy’’ [TW] AND
‘‘surgery’’ [TW])
2. Second step
‘‘Incidence’’ [MESH] OR ‘‘Follow-Up Studies’’ [MESH]
OR ‘‘Prognosis’’ [MeSH:NOEXP] OR ‘‘prognos*’’ [TW]
OR ‘‘predict*’’ [TW] OR ‘‘course’’ [TW] OR ‘‘outcome’’
[TW] OR ‘‘Survival Analysis’’ [MH:NOEXP]
3. Third step
‘‘randomized controlled trial’’ [PTYP] OR ‘‘random*’’
[TW] OR (‘‘double’’[TW] AND ‘‘blind*’’ [TW]) OR
‘‘placebo’’ [TW] OR ‘‘drug therapy’’ [SH] OR ‘‘anticon-
vulsants’’ [SH] OR ‘‘antiepileptic drugs ‘‘ [SH] OR ‘‘thera-
peutic use’’ [SH:NOEXP] OR ‘‘cohort studies’’ [MESH]
OR ‘‘risk’’ [MESH] OR (‘‘odds’’ [TW] AND ‘‘ratio*’’
[TW]) OR (‘‘relative’’ [TW] AND ‘‘risk’’ [TW]) OR ‘‘case
control*’’ [TW] OR ‘‘case-control studies’’ [MESH]
4. Limits
1947–2007, Human, Journal article
Epilepsia, 50(6):1301–1309, 2009
doi: 10.1111/j.1528-1167.2008.01997.x