J Neurosurg 115:1169–1174, 2011

Predictors of seizure freedom in the surgical treatment of

supratentorial cavernous malformations

Clinical article
Dario J. Englot, M.D., Ph.D., Seunggu J. Han, M.D., Michael T. Lawton, M.D.,
and Edward F. Chang, M.D.

Department of Neurological Surgery, University of California, San Francisco, California

Object. Seizures are the most common presenting symptom of supratentorial cerebral cavernous malformations
(CCMs) and progress to medically refractory epilepsy in 40% of patients. Predictors of seizure freedom in the resec-
tion of CCMs are incompletely understood.
Methods. The authors systematically reviewed the published literature on seizure freedom following the resec-
tion of supratentorial CCMs in patients presenting with seizures. Seizure outcomes were stratified across 12 potential
prognostic variables. A total of 1226 patients with supratentorial CCMs causing seizures were identified across 31
predominantly retrospective studies; 361 patients had medically refractory epilepsy.
Results. Seventy-five percent of the patients were seizure free after microsurgical lesion removal, whereas 25%
continued to have seizures. All patients had had preoperative seizures and > 6 months of postoperative follow-up.
Modifiable predictors of postoperative seizure freedom included gross-total resection (OR 36.6, 95% CI 8.5–157.5)
and surgery within 1 year of symptom onset (OR 1.83, 95% CI 1.30–2.58). Additional prognostic indicators of a
favorable outcome were a CCM size < 1.5 cm (OR 15.4, 95% CI 5.2–45.4), the absence of multiple CCMs (OR 2.02,
95% CI 1.13–3.60), medically controlled seizures (OR 2.38, 95% CI 1.29–4.39), and the lack of secondarily general-
ized seizures (OR 3.33, 95% CI 2.09–5.30). Other factors, including extended resection of the hemosiderin ring, were
not significantly predictive.
Conclusions. In the surgical treatment of supratentorial CCMs, gross-total resection and early operative inter-
vention may improve seizure outcome. While surgery should not be considered the first-line treatment for CCM-
related epilepsy, it is important to understand the variables associated with seizure freedom in CCM resection given
the considerable morbidity and diminished quality of life associated with epilepsy. (DOI: 10.3171/2011.7.JNS11536)

Key Words      •      cavernoma      •      cavernous angioma      •      epilepsy      •

resection      •      seizure      •      vascular disorders

C
erebral cavernous malformations are endothe-
lial-lined vascular malformations composed of
dilated sinusoids filled with blood and no inter-
vening brain tissue and may be associated with intracra-
nial hemorrhage.4,39,42 Seizures, the most common pre-
senting symptom of supratentorial CCMs, are thought to
arise from the excitotoxic effects of blood products on
perilesional parenchyma.52–54 Overall, epilepsy affects
35%–70% of patients with CCMs, with approximately
40% of individuals progressing to medically refractory
epilepsy.13,37,44 It is well known that epilepsy can dramati-
cally diminish quality of life with serious morbidity and
that AEDs frequently have unfavorable side-effect pro-
files.10,18,46 Therefore, while most authors examining the
natural history and treatment of CCMs focus on the risk
of intracranial hemorrhage,34,39,41 abolishing seizures is an
Abbreviations used in this paper: AED = antiepileptic drug; CCM
= cerebral cavernous malformation; ECoG = electrocorticography;
GTR = gross-total resection.
important and often underappreciated treatment goal in
managing these lesions.
Factors associated with seizure control in the re-
section of supratentorial CCMs remain incompletely
understood as a result of patient diversity, small sample
sizes, and disagreement about operative approaches. For
instance, there is controversy regarding whether exci-
sion of the hemosiderin-stained parenchymal ring typi-
cally surrounding CCMs is necessary to achieve seizure
freedom6,7,28,49,56,57 and whether an expedited surgical ap-
proach predicts improved seizure outcome.1,8,14 Neither is
it fully understood how the preoperative seizure profile
might predict postoperative seizure recurrence.13,37 The
systematic consolidation and analysis of predictors of sei-
zure freedom as reported across various smaller studies
may help to clarify these issues.
Our goal was to perform a quantitative and compre-
hensive systematic literature review of seizure outcomes
following the resection of supratentorial CCMs associat-
ed with seizures. We analyzed the proportion of patients

J Neurosurg / Volume 115 / December 2011 1169


in whom complete seizure freedom was achieved after
surgery, and we stratified outcomes according to several
potential prognostic variables.
Methods
Article Selection and Data Extraction
We conducted a PubMed search of articles published
between 1985 and February 2011 by using the following
search terms alone and in combination: “seizure,” “epi-
lepsy,” “cavernous malformation,” “cavernous angioma,”
“cavernous hemangioma,” “cavernoma,” “surgery,” and
“resection.” References from all selected papers were
further examined for additional suitable studies and to
identify possible patient duplication. We selected only
those reports of patients harboring supratentorial CCMs
causing preoperative seizures, in which postoperative
seizure status was a primary outcome and the follow-up
spanned a minimum of 6 months for all patients. Studies
were excluded if they included fewer than 5 patients, re-
ported only redundant data, did not disaggregate seizure
outcomes, were not written in English, or consisted of a
review. Studies that considered lesions other than CCMs
or examined infratentorial lesions were included in part
only if the outcomes related to other lesion types could
be excluded. Outcomes from all studies were disaggre-
gated across 12 variables where possible: 1) patient age
at surgery (< 18 vs ≥ 18 years old); 2) sex; 3) CCM loca-
tion (temporal lobe vs extratemporal); 4) CCM laterality;
5) CCM size (maximum diameter < 1.5 vs ≥ 1.5 cm); 6)
CCM multiplicity (resection of solitary vs multiple le-
sions); 7) preoperative seizure control on medication
(controlled vs refractory); 8) seizure semiology (partial
seizures only vs secondarily generalized seizures); 9) du-
ration of epilepsy before surgery (≤ 1 vs > 1 year); 10)
extent of resection (gross total vs subtotal); 11) whether
perilesional hemosiderin-stained parenchyma was ex-
cised (lesionectomy only vs additional corticectomy); and
12) whether awake ECoG was used intraoperatively. Ce-
rebral cavernous malformation size was dichotomized at
1.5 cm because prior evidence has suggested a more fa-
vorable postoperative seizure outcome with lesions below
this size.12 Gross-total resection was defined based on the
lack of residual lesion both intraoperatively and on post-
operative imaging. Seizure outcomes were defined using
the Engel classification scheme.22
Statistical Analysis
Separate meta-analyses were performed on calculat-
ed pooled rates of seizure freedom (Engel Class I) versus
persistent seizures (Engel Class II–IV) for each variable.
Initial between-group comparisons were performed us-
ing the Pearson chi-square test. Binary logistic regression
analysis was then used to evaluate the variables found to
be significant on chi-square testing by using a backward
stepwise approach. Odds ratios were calculated with a
95% confidence interval. The Friedman test and Kendall
W test were used to analyze data heterogeneity between
studies to ensure that a fixed-effects model was appropri-
ate, and the Cox and Snell R-squared values were calcu-
lated to ensure goodness-of-fit of the applied model. The
1170
D. J. Englot et al.
Begg funnel plot method was applied to detect the pos-
sible effect of publication bias. Missing values were ad-
dressed by listwise deletion, and multiple imputation was
not used. Given the number of comparisons being made,
the level of significance was set at 0.02 for all analyses.
Statistical analysis was performed using SPSS version 17
software (SPSS, Inc.).
Results
We identified 1226 patients across 31 studies on sei-
zure control following the resection of supratentorial
CCMs.1–3,5,6,8,9,13,15,16,19–21,23,24,26–29,33,35,37,38,43,47,49–51,55–57 Three
studies identified on initial query were excluded because
of a sample size smaller than 5 patients, the lack of seizure
outcome disaggregation, or data redundancy, respectively.
All included papers were retrospective analyses, except for
one prospective observational study, and are listed in Table
1. No controlled trials of seizure outcomes in CCM resec-
tion were identified. All patients had experienced lesion-
related seizures preoperatively and were followed up for at
least 6 months after surgery, with a mean follow-up rang-
ing from > 12 to 97 months within the individual studies.
Across individual data sets, 33%–100% of patients were
seizure free after resection, as summarized in Fig. 1. Over-
all, 915 patients (75%) were free of seizures after surgery
(Engel Class I), whereas 311 (25%) continued to have sei-
zures (Engel Classes II–IV).
Seizure outcomes were stratified across 12 variables
of interest where disaggregation was possible, as summa-
rized in Table 2. We first looked at patient demographics
and observed similar rates of postoperative seizure free-
dom among pediatric versus adult patients (75% vs 73%
seizure free, respectively) and among female versus male
patients (71% each). Next, we examined factors related to
the lesion. There was no statistical difference in seizure
outcomes between patients with temporal lobe versus ex-
tratemporal CCMs, nor with left versus right hemispheric
lesions. However, we did find that individuals with smaller
(< 1.5 cm) CCMs attained a dramatically higher seizure
control rate (86%) than did those with a lesion size ≥ 1.5
cm (29% seizure free; p < 0.001). Resection of a solitary
CCM was also predictive of a favorable outcome: while
71% of those with a solitary lesion became seizure free
after surgery, only 55% of those with multiple resected
CCMs attained this outcome (p < 0.02).
We next analyzed whether characteristics related
to epilepsy predicted the postoperative seizure status.
It was noted that individuals with preoperative seizures
controlled with AEDs attained a higher rate of seizure
freedom after CCM resection (84%) than did those with
medically refractory epilepsy (69%; p < 0.01; Table 2).
Seizure semiology also predicted variable outcomes, as
81% of patients experiencing only partial seizures be-
came seizure free postoperatively, compared with only
56% of individuals with secondarily generalized events
(p < 0.001). Furthermore, a shorter preoperative history
of seizures (≤ 1 year) prognosticated a better result (81%
seizure freedom) than did a longer history (> 1 year) of
epilepsy (p < 0.001).
Finally, factors related to surgical intervention were
examined for possible outcome prognostication. Gross-
J Neurosurg / Volume 115 / December 2011
Seizures after cavernoma resection
TABLE 1: Studies included in analysis of seizure freedom
following treatment for supratentorial CCMs

Authors & Year No. of Cases Mean Follow-Up (mos)

Acciarri et al., 1995  36 71
Acciarri et al., 2009  29 57
Alexiou et al., 2009  14 71
Baumann et al., 2006  31 34
Baumann et al., 2007 168 25
Cappabianca et al., 1997  35 >24
Casazza et al., 1996  47 48
Chang et al., 2009  44 32†
Cohen et al., 1995  50 60
Consales et al., 2010*   5 48†
D’Angelo et al., 2006  69 55 Fig. 1.  Scatterplot demonstrating seizure freedom after CCM resec-
Daglioglu et al., 2010   6 26 tion across 31 studies. Each point on the plot represents 1 study, orga-
nized from 1 to 31 in order of decreasing sample size. Seizure freedom
Dodick et al., 1994  20 36 (Engel Class I outcome) ranged from 33% to 100%. The summary box-
Ferrier et al., 2007  19 >12 plot (right) depicts the median (center line), 25th percentile, and 99th
Ferroli et al., 2006 163 48 percentile of reported seizure freedom rates across all studies, with
outliers (X).
Folkersma & Mooij, 2001   7 40
Giulioni et al., 1995  11 68
of 15.4 (95% CI 5.2–45.4) and 2.02 (95% CI 1.13–3.60),
Hammen et al., 2007  30 24 respectively. Positive predictors related to preoperative
Hsu et al., 2007  15 92 seizure characteristics included adequate medical control
Kivelev et al., 2011  39 72† on AEDs (OR 2.38, 95% CI 1.29–4.39), the presence of
Kraemer et al., 1998  15 66 partial seizures only (OR 3.33, 95% CI 2.09–5.30), and
Moran et al., 1999  16 38 symptom duration ≤ 1 year (OR 1.83, 95% CI 1.30–2.58).
Finally, achieving a gross-total lesionectomy also prog-
Noto et al., 2005  15 64
nosticated seizure control (OR 36.6, 95% CI 8.5–157.5).
Rocamora et al., 2009  11 >24
Shih & Pan, 2005  14 46
Stavrou et al., 2008  57 97 Discussion
Upchurch et al., 2010  12 51
Seizures are the most common presenting symptom
Van Gompel et al., 2009  87 37 in patients with supratentorial CCMs and can progress to
Xia et al., 2009  24 29 medically refractory epilepsy in approximately 40% of
Yeon et al., 2009  60 31 cases.13,37,44 While most studies of CCMs focus on the risk
Zevgaridis et al., 1996  77 39 of intracranial hemorrhage, eliminating the seizure bur-
den in patients with cavernoma and epilepsy can reduce
*  Prospective observational study. Other studies are all retrospective. disability and improve quality of life, and thus is an im-
† Median. portant goal of treatment. To identify the epidemiological
and therapeutic predictors of seizure freedom in the re-
total lesionectomy resulted in a dramatically better section of supratentorial CCMs, we performed a system-
chance of seizure control (77%) than did subtotal CCM atic literature review of 1226 CCM patients with lesion-
resection, after which only 8% of patients were seizure related seizures and stratified the seizure outcomes across
free (p < 0.001; Table 2). However, patients were equally various potentially prognostic variables. Overall, 75% of
likely to stop seizing after undergoing lesionectomy with patients became seizure free after resection, suggesting
or without additional excision of surrounding hemosid- that a microsurgical approach often leads to a favorable
erin fringe (75% vs 76% seizure free, respectively). In outcome but also indicating considerable room for im-
determining whether intraoperative ECoG affected out- provement. Most importantly, we found that potentially
come, we noted that its use led to a somewhat higher rate modifiable predictors of postoperative seizure control in-
of seizure freedom (78%) than did surgery without ECoG cluded both GTR (vs subtotal lesionectomy) and a shorter
(68%), but this difference did not reach our threshold for preoperative history of epilepsy (≤ 1 year). These factors
statistical significance (p = 0.03). reveal that achieving a gross-total lesionectomy and early
Binary logistic regression analyses were used to fur- intervention are important goals in cases in which resec-
ther scrutinize the 6 variables found to be statistically sig- tion is deemed as an appropriate and safe treatment for a
nificant on chi-square testing, as summarized in Table 3. CCM. Gross-total resection can be challenging in deep
A CCM size < 1.5 cm and a solitary lesion significantly or eloquent brain regions, but various microsurgical ap-
predicted postoperative seizure freedom, with odds ratios proaches and trajectories have been recently described

J Neurosurg / Volume 115 / December 2011 1171

 D. J. Englot et al.
TABLE 2: Seizure outcomes stratified across factors of interest TABLE 3: Predictors of seizure freedom after CCM resection

No. (%) Parameter OR 95% CI p Value

Engel Engel Classes CCM size <1.5 cm 15.4 5.2–45.4 <0.001
Parameter Class I II–IV c2 p Value
single CCM only 2.02 1.13–3.60 <0.02
age in yrs seizures medically controlled 2.38 1.29–4.39 <0.01
  <18 71 (75) 24 (25) 0.1 0.79 partial seizures only 3.33 2.09–5.30 <0.001
  ≥18 228 (73) 84 (27) seizures for ≤1 yr 1.83 1.30–2.58 <0.001
sex gross-total lesionectomy 36.6 8.5–157.5 <0.001
 F 98 (71) 41 (29) 0.0 0.90
 M 100 (71) 40 (29)
stained parenchyma surrounding the lesion. Some groups
CCM location have reported improved seizure outcomes with an ex-
 temporal 194 (69) 87 (31) 0.4 0.61 tended lesionectomy including the hemosiderin ring,6,28,49
 extratemporal 274 (71) 111 (29) whereas others have demonstrated no additional benefit
CCM laterality over pure lesionectomy.56,57 Overall, we found no differ-
 lt 63 (63) 37 (37) 2.5 0.11
ence in the rates of seizure freedom after pure lesionec-
tomy versus inclusion of the hemosiderin fringe. This
 rt 65 (74) 23 (26) finding suggests that a more extensive resection beyond
CCM size in cm gross-total lesionectomy may not confer any additional
  <1.5 43 (86) 7 (14) 28.9 <0.001† benefit in seizure control but may be associated with in-
  ≥1.5 10 (29) 25 (71) creased neurological morbidity. Given the conflicting
CCM multiplicity findings in previous reports, however, additional prospec-
tive data should be sought to further clarify this issue.
 single 410 (71) 167 (29) 5.8 <0.02† Not surprisingly, it was also noted that a greater dis-
 multiple 28 (55) 23 (45) ease burden was associated with higher rates of postop-
seizure control* erative seizures. Patients with multiple CCMs were less
 controlled 73 (84) 14 (16) 8.0 <0.01† likely to attain seizure freedom after resection than were
 refractory 248 (69) 113 (31) those who had harbored a single cavernoma. Moreover,
both the presence of secondarily generalized seizures and
seizure semiology
poor seizure control on AEDs predicted a worse outcome.
  partial only 158 (81) 38 (19) 26.8 <0.001† In mesial temporal lobe epilepsy, the most common form
 generalized 95 (56) 76 (44) of epilepsy, secondary generalization has been associated
duration of epilepsy with postoperative seizure recurrence,30,31,36 and the pres-
  ≤1 year 313 (81) 72 (19) 12.3 <0.001† ence of generalized seizures has been linked to more sig-
nificant mesial temporal atrophy.11,17 It is therefore plau-
  >1 year 256 (70) 108 (30)
sible that CCM patients with more severe epileptic events
extent of lesionectomy have higher rates of dual pathology,25,48 which may con-
 GTR 506 (77) 152 (23) 57.3 <0.001† tinue to drive seizures after lesionectomy. More evidence
 subtotal 2 (8) 22 (92) will be needed to further evaluate this possibility.
hemosiderin excision No differences in seizure outcome were observed in
adults versus children, males versus females, or with cav-
  lesionectomy only 224 (76) 71 (24) 0.1 0.82
ernomas located in the left versus the right hemisphere
  w/ corticectomy 352 (75) 116 (25) or the temporal lobe versus the extratemporal region. Fi-
intraop ECoG nally, the use of intraoperative ECoG was associated with
 used 96 (78) 27 (22) 4.6 0.03 a 10% higher rate of postoperative seizure control, but
  not used 265 (68) 125 (32) this difference was not significant. Note, however, that it
total 915 (75) 310 (25)
is not known whether cases in which ECoG is used are
associated a priori with more severe epilepsy or with a
*  Seizures medically controlled or refractory preoperatively. lesion less amenable to GTR given the involvement of
†  Significant value (p < 0.02). eloquent structures, and thus potentially confounding this
result. Furthermore, insufficient data were available to
specifically investigate whether ECoG might be of var-
to facilitate safe access to supratentorial CCMs in these ied benefit in patients with medically refractory versus
locations.12 Finally, our finding that patients with larger controlled epilepsy. Prospective investigations with com-
CCMs (≥ 1.5 cm) continued to seize more often than parable patient characteristics will be needed to further
those with smaller lesions (< 1.5 cm) also supports early address the benefit of intraoperative ECoG for epilepsy
surgical treatment, as some cavernomas have demonstrat- related to CCMs.
ed the potential to grow in size over time.32,40,45 There are several limitations to the present system-
One controversy in the operative treatment of su- atic review. While these data represent a useful summary
pratentorial CCMs is whether to excise the hemosiderin- of seizure control following supratentorial CCM resec-

1172 J Neurosurg / Volume 115 / December 2011

Seizures after cavernoma resection
tion in a large patient population, they are limited by the
quality of the data published by others. We cannot ascer-
tain the validity of subjectively defined variables reported
in the original articles, which may have an important in-
fluence on our findings. All except one of the analyzed
papers featured retrospective uncontrolled studies, and 3
articles included fewer than 10 patients, introducing the
possibility of bias in result reporting and interpretation.
Moreover, the exclusion of non-English papers may lead
to the omission of useful data. As no controlled trials of
seizure outcome in CCM resection have been performed
to our knowledge, this study cannot be considered a for-
mal meta-analysis of trial data, but rather is a systematic
review of available literature. While a single, large pro-
spective series with post hoc testing of potential interac-
tions would certainly be welcomed, the strength of the
present evaluation lies in the ability to pool a large num-
ber of cases, which would be difficult to achieve even in
a multiinstitutional trial. Finally, many interesting issues
were not addressed in our study, such as a comparative
evaluation of microsurgery versus stereotactic radiosur-
gery to treat CCMs causing seizures, but will certainly
contribute to excellent questions in future investigations.
Conclusions
In summary, CCMs are vascular brain lesions that
most commonly appear with seizures and often result in
medically refractory epilepsy. In a systematic review of
1226 patients with supratentorial CCMs, we found that
early operative intervention and GTR significantly im-
proved seizure outcome. Individuals with a single lesion
and smaller lesions, as well as those with pharmacologi-
cally controlled epilepsy and the absence of secondarily
generalized events, were also more likely to attain post-
operative seizure freedom. Resection should not be con-
sidered a first-line treatment for CCM-related epilepsy,
because seizures can often be controlled with AEDs, and
because many patients are not good surgical candidates.
However, given the considerable effects that epilepsy can
have on a patient’s quality of life, it is critical to under-
stand the demographic and treatment variables associated
with seizure control in CCM resection and to incorporate
that knowledge into our neurosurgical practices and pa-
tient discussions.
Disclosure
The authors report no conflict of interest concerning the mate-
rials or methods used in this study or the findings specified in this
paper.
Author contributions to the study and manuscript prepara-
tion include the following. Conception and design: Chang, Englot.
Acquisition of data: Englot. Analysis and interpretation of data:
all authors. Drafting the article: Englot. Critically revising the
ar­ticle: all authors. Reviewed submitted version of manuscript: all
au­thors. Approved the final version of the manuscript on behalf of
all authors: Chang. Statistical analysis: Englot. Study supervision:
Chang, Law­ton.
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Manuscript submitted March 28, 2011.
Accepted July 12, 2011.
Please include this information when citing this paper: published
online August 5, 2011; DOI: 10.3171/2011.7.JNS11536.
Address correspondence to: Edward F. Chang, M.D., Department
of Neurological Surgery, University of California, San Francisco,
505 Parnassus Avenue, Box 0112, San Francisco, California 94143-
0112. email: ChangED@neurosurg.ucsf.edu.
J Neurosurg / Volume 115 / December 2011