Peer-Review Reports
CEREBROVASCULAR
Seizures After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review of
Outcomes
Daniel M. S. Raper1, Robert M. Starke 2, Ricardo J. Komotar 3, Rodney Allan 4, E. Sander Connolly, Jr.5
Key words
䡲 Aneurysm
䡲 Endovascular
䡲 Intracranial
䡲 Microsurgery
䡲 Seizure
Abbreviations and Acronyms
ACA: Anterior cerebral artery
ACommA: Anterior communicating artery
AED: Antiepileptic drug
aSAH: Aneurysmal subarachnoid hemorrhage
HH: Hunt and Hess
ISAT: International Subarachnoid Aneurysm trial
MCA: Middle cerebral artery
SAH: Subarachnoid hemorrhage
From the 1Royal North Shore
Hospital, Sydney, New South
Wales, Australia; 2Department of Neurological Surgery,
University of Virginia, Charlottesville, Virginia, USA;
3
Department of Neurological Surgery, University of Miami,
Miami, Florida, USA; 4Department of Neurosurgery, Royal
Prince Alfred Hospital, Sydney, New South Wales,
Australia; and 5Department of Neurological Surgery,
Columbia University, New York, New York, USA
To whom correspondence should be addressed:
Daniel M. S. Raper, M.B.B.S.
[E-mail: drap7157@uni.sydney.edu.au]
Citation: World Neurosurg. (2013) 79, 5/6:682-690.
http://dx.doi.org/10.1016/j.wneu.2012.08.006
Journal homepage: www.WORLDNEUROSURGERY.org
Available online: www.sciencedirect.com
1878-8750/$ - see front matter © 2013 Elsevier Inc.
All rights reserved.
INTRODUCTION
Seizures are a well-recognized complica-
tion after aneurysmal subarachnoid hemor-
rhage (aSAH), and have been correlated
with higher aneurysm grade, lower Glas-
gow Coma Scale score at presentation, ex-
tent of subarachnoid blood on computed
tomography, and rebleeding (2, 18, 29, 40,
53). Early studies reported seizures in over
10% of survivors of aSAH; these were more
likely in younger patients, those with mid-
dle cerebral artery (MCA) aneurysms, and
those with coexisting intracerebral hemor-
rhage (11, 46). Seizures have been observed
after both microsurgical clipping and endo-
vascular coiling (9, 13). In the International
682 www.SCIENCEDIRECT.com
䡲 OBJECTIVE: The risk for early and late seizures after aneurysmal subarachnoid
hemorrhage (aSAH), as well as the effect of antiepileptic drug (AED) prophylaxis and
the influence of treatment modality, remain unclear. We conducted a systematic
review of case series and randomized trials in the hope of furthering our under-
standing of the risk of seizures after aSAH and the effect of AED prophylaxis and
surgical clipping or endovascular coiling on this important adverse outcome.
䡲 METHODS: We performed a MEDLINE (1985–2011) search to identify random-
ized controlled trials and retrospective series of aSAH. Statistical analyses of
categorical variables such as presentation and early and late seizures were
carried out using ␹2 and Fisher exact tests.
䡲 RESULTS: We included 25 studies involving 7002 patients. The rate of early
postoperative seizure was 2.3%. The rate of late postoperative seizure was 5.5%.
The average time to late seizure was 7.45 months. Patients who experienced a
late seizure were more likely to have MCA aneurysms, be Hunt/Hess grade III,
and be repaired with microsurgical clipping than endovascular coiling.
䡲 CONCLUSIONS: Despite improved microsurgical techniques and antiepileptic
drug prophylaxis, a significant proportion of patients undergoing aneurysm
clipping still experience seizures. Seizures may occur years after aneurysm
repair, and careful monitoring for late complications remains important. Further-
more, routine perioperative AED use does not seem to prevent seizures after SAH.
Subarachnoid Aneurysm trial (ISAT) and evidence of benefit (4). Furthermore pheny-
subsequent subgroup analyses, patients toin, which has traditionally been the most
treated with clipping had a significantly commonly used AED for aneurysm pa-
higher risk of late seizure than those treated tients, has a variety of adverse effects and
with coiling (32, 42, 49). Nevertheless, the has been correlated with poor functional
influence of treatment modality on either outcomes and cognitive status after sub-
early or late seizure outcomes has not been arachnoid hemorrhage (SAH) (33). Never-
assessed in a systematic review of the liter- theless, in a 2002 survey conducted by the
ature. American Association of Neurological Sur-
The administration of prophylactic anti- geons, 24% of neurosurgeons surveyed
epileptic drugs (AEDs) has in the past been routinely prescribed AEDs for 3 months af-
a standard protocol for patients undergoing ter SAH regardless of whether seizures oc-
many neurosurgical procedures. More re- curred at presentation, in hospital, or not at
cently, however, routine use of AEDs for all (3, 13, 17, 18). The use of AEDs as a
aSAH patients has come under question primary prophylactic measure in aSAH pa-
(45). Low seizure rates have been reported tients thus remains controversial.
in series of patients with aSAH (9, 11). In In order to gain a better understanding of
reviewing these and other modern experi- the risk for early and late seizures after
ences, the Stroke Council of America guide- aSAH, and to provide a quantitative supple-
lines, published in 2009, recommended mentation to recent consensus statements
against routine perioperative AED use in on the topic (26), we believe it useful to
ruptured aneurysms because of a paucity of survey the modern published literature. To
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DANIEL M. S. RAPER ET AL.
this end, we have performed a systematic
review of the available published reports of
outcomes following aneurysm repair after
SAH in order to gain a more comprehensive
assessment of the risk of seizure and the
influence of AED prophylaxis and treatment
modality.
MATERIALS AND METHODS
Study Selection
We performed a modern literature search
using the Ovid gateway of the MEDLINE
database between the years 1985 and 2010.
The following key words were queried sin-
gly and/or in combination: seizure, sub-
arachnoid, hemorrhage, epilepsy, aneu-
rysm, antiepileptic, anticonvulsant, outcome,
surgery. The search was limited to studies
published in English, and humans were
specified as the study category. No spe-
cific review protocol was used for this sys-
tematic review.
Eligibility criteria were limited by the na-
ture of existing literature on this topic,
which consists largely of retrospective case
series. To gain a more accurate reflection
of seizure incidence using modern micro-
surgical and endovascular techniques, only
reports published after 1985 were included
in this review. All publications reporting
seizure outcomes after surgery or endovas-
cular intervention for ruptured intracranial
aneurysms were selected, whereas editori-
als, commentaries, and review articles were
not, because they did not include original
data. Series that included patients with un-
ruptured aneurysms or patients with a past
history of epilepsy were also excluded from
this analysis. To avoid duplication of pa-
tients, in cases in which multiple articles
were published from the same authors or
the same institution, only the report with
the largest relevant cohort was included. A
manual search for manuscripts was also
conducted by scrutinizing references from
identified manuscripts, major neurosurgi-
cal journals and texts, and personal files.
The date of the last search was March 2011.
Data Extraction
Included studies were reviewed and care-
fully scrutinized for study design, method-
ology, and patient characteristics. The total
number of patients for each study was ex-
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SEIZURES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE
tracted and divided into cohorts according
to aneurysm location and treatment strat-
egy. Data for all patients were recorded
when available, including mean age, sex,
aneurysm location, presentation seizure,
and SAH grade. Presentation seizures were
defined as those occurring before the first
intervention for SAH. Early seizures were
defined as those that occurred after inter-
vention during the initial hospital stay. Late
seizures were defined as those that occurred
after discharge from hospital. Because the
series in this review included randomized
trials as well as prospective and retrospec-
tive case series, an assessment of bias was
made only on the outcome level rather than
at the individual study level. The interpreta-
tion of these results is limited by this un-
quantified level of bias, and makes our
systematic review a synthesis of level 3 evi-
dence only.
Statistical Analysis and Systematic
Analysis
Data from the individual studies were com-
bined by cohort and then compared. Statis-
tical analyses of categorical variables were
carried out using ␹2 and Fisher exact tests as
appropriate. Because there were significant
differences between cohorts, analysis of
heterogeneity was not carried out. Values of
P ⱕ .05 were considered statistically signif-
icant.
RESULTS
Study Selection and Study
Characteristics
A total of 87 published studies since 1985
were identified through our initial MED-
LINE database search. After removal of du-
plicates, all records were screened by review
of abstracts for suitability. The full text of all
records with reference to aneurysm and sei-
zure was downloaded and filtered for men-
tion of seizure outcomes using a combina-
tion of search terms (epilep*, seiz*,
convul*, etc.) Applicable records were thor-
oughly reviewed for final inclusion or exclu-
sion. Altogether, 62 records were rejected
from our review because they did not in-
clude original data, did not report seizure
outcomes, or did not differentiate between
ruptured and unruptured aneurysms. Stud-
ies were analyzed with respect to overall sei-
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PEER-REVIEW REPORTS
zure outcomes, as well as seizure outcomes
CEREBROVASCULAR
between cohorts that received AED prophy-
laxis vs. those that received no AED prophy-
laxis, and between cohorts of aneurysms
that were clipped vs. those that were coiled.
A total of 25 studies reported seizure out-
comes after aSAH. Fourteen studies re-
ported outcomes among cohorts of aSAH
patients who received AED prophylaxis (3,
10, 12, 13, 16, 19, 22, 23, 27, 34, 41, 44, 50,
53), 3 studies reported outcomes in those
who did not receive AED prophylaxis (6, 7,
39), and 3 studies compared cohorts treated
with AED or no AED prophylaxis (28, 38,
43). Fifteen studies reported outcomes
among cohorts of aSAH patients who were
clipped (3, 6, 7, 10, 16, 19, 22, 23, 27, 30, 34,
39, 40, 53), 1 study reported outcomes in
those who were coiled (9), and 3 studies
compared cohorts who were clipped and
coiled, reporting seizure outcomes (28, 32,
43). A total of 25 studies and 7002 patients
were included in this review.
Characteristics and primary findings of
the 25 included studies of seizures in pa-
tients with aneurysmal SAH are summa-
rized in Table 1. Regarding study design, 21
articles were retrospective (3, 7, 9, 10, 12, 16,
19, 22, 23, 27, 28, 34, 38-41, 43, 44, 50, 51,
53), 3 were prospective (13, 16, 30), and
there was 1 randomized controlled trial
(32).
Patient Characteristics
Patient characteristics of the whole cohort,
as well as cohorts of clipped vs. coiled and
AED prophylaxis vs. no AED prophylaxis,
are reported in Table 2. In total there were
7002 patients, mean age 51.3, mean fol-
low-up 46.6 months, 37.5% male. Aneu-
rysms were located most commonly in the
anterior communicating artery (ACommA)
and MCA, and were evenly split between
Hunt and Hess (HH) grades I, II, and III. In
the clipped cohort there were 4378 patients,
mean age 49.5, mean follow-up 50.9
months, 40.5% male. Aneurysms were lo-
cated in the anterior circulation in 93.2%,
most commonly HH grade II. In the coiled
cohort there were 1418 patients, mean age
52.2, mean follow-up 43.0 months, 36.6%
male. Aneurysms were located in the ante-
rior circulation in 71.1%; the HH grade was
not reported in any reports of coiled aneu-
rysms. The 2 cohorts did not differ signifi-
cantly in any patient or aneurysm character-
istics. In the AED cohort there were 3232
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DANIEL M. S. RAPER ET AL. SEIZURES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE

Table 1. Study Characteristics of Seizures After Aneurysmal SAH

CEREBROVASCULAR

Mean Hunt and Hess Grade

Study Patient Age AED Follow- Presentation Early Late
Author and Year Design Number Approach Male (years) I II III IV V Use Up Seizure Seizure Seizure

Ise et al., 1985 (22) Retro 192 Open 82 51.1 62 62 55 13 0 192 32.9 13 — 18
Keranen et al., 1985 (23) Retro 177 Open 82 43.8 81 54 42 177 — — — 25
Sundaram and Chow, Retro 104 — — — — — — — — — — 19 7 5
1986 (51)
Fabinyi and Artiola- Retro 265 Open — — — — — — — 199 — 0 4 5
Fortuny, 1980 (16)
Ohman, 1990 (39) Retro 307 Open — 45.2 77 109 56 25 11 0 — — — 29
Ukkola and Heikkinen, Retro 183 Open — — — — — — — — 43.2 — 1 13
1990 (53)
Bidzinski et al., 1992 (6) Pros 118 Open — — — — — — — 0 21 — — 8
Baker et al., 1995 (3) Retro 200 Open — — 70 46 60 21 3 200 28.8 — 3 6
Pinto et al., 1996 (41) Retro 253 — — — — — — — — 61 — 16 — 1
Ogden et al., 1997 (38) Retro 123 — 42 48.8 — — — — — 52 — 2 9 13
Hayashi et al., 1999 (19) Retro 116 Open — — 11 57 24 21 3 116 — — 4 4
Olafsson et al., 2000 (40) Retro 44 Open — — — — — — — — 277.2 10 — 11
Rhoney et al., 2000 (44) Retro 94 Open 29 47.9 — — — — — 94 — 17 5 8
Naso et al., 2001 (34) Retro 53 Open — — 42 11 53 — — 1 0
Buczacki et al., 2004 (7) Retro 472 Open 157 53 — — — — — 0 — — — 23
Byrne et al., 2003 (9) Retro 243 Endo 90 50.9 — — — — — — 21.1 26 — 4
Claassen et al., 2003 (13) Pros 219 — — — — — — — — 219 — — 8 27
Lin et al., 2003 (27) Retro 217 Open 85 49.3 — — — — — 217 78.7 22 4 21
Mitchell et al., 2005 (30) Pros 5 Open — — — — — — — — — — — 1
Molyneux et al., RCT 2143 O/E — — — — — — — — 48 14 49 109
2005 (32)
Chumnanvej et al., Retro 453 — 141 54.3 153 134 92 71 453 — — 8 15
2007 (12)
Lin et al., 2008 (28) Retro 137 O/E 44 55.8 — — — — — — — 5 8 1
Choi et al., 2009 (10) Retro 547 Open 228 — 128 96 4 547 — 51 6 30
Shah and Husain, Retro 176 — 63 58.2 111 51 14 176 — 5 0 0
2009 (50)
Raper et al., 2011 (43) Retro 161 O/E 59 54.6 — — — — — 92 — 27 4 9
SAH, subarachnoid hemorrhage; AED, antiepileptic drug; Retro, retrospective: Pros, prospective; RCT, randomized controlled trial; O/E, open and endoscopic.

patients, mean age 51.7, mean follow-up
46.8 months, 39.2% male. Aneurysms were
located in the anterior circulation in 90.9%,
most commonly HH grade III. In the no
AED cohort there were 1165 patients, mean
age 51.2, mean follow-up 21 months, 33.3%
male. Aneurysms were located in the ante-
rior circulation in 96.1%, most commonly
HH grade I.
There were a number of significant dif-
ferences between the AED and no AED co-
horts. Those not receiving AEDs had a
higher incidence of anterior communicat-
ing artery, MCA, and posterior communi-
cating artery aneurysms and a lower inci-
dence of anterior cerebral artery (ACA),
internal carotid artery, and posterior cere-
bral artery aneurysms. This group likewise
had lower incidence of HH grades III to V,
but a higher incidence of grade II aneu-
rysms. Between the clipped and coiled
groups, there were also a number of signif-
icant differences. The clipped cohort had a
higher incidence of anterior communicat-
ing artery, ACA, MCA, and posterior cere-
bral artery aneurysms, and a lower inci-
dence of posterior communicating, basilar
apex, and other posterior circulation aneu-
rysms.
Antiepileptic Drug Characteristics
Overall, AED prophylaxis was used in 3244
of 4463 reported cases (72.7%). The aver-
age time of AED use was 8.2 months (range:
5 days to 25.8 months). Among the cohort

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DANIEL M. S. RAPER ET AL. SEIZURES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE

Table 2. Patient and Aneurysm Characteristics in Aneurysmal SAH Studies

CEREBROVASCULAR
AED Prophylaxis Treatment Modality

All Patients AED No AED P Value Clip Coil P Value

Patient characteristics
Total patients 7002 3232 1165 4378 1418
Mean age 51.3 51.7 51.2 49.5 52.2
Male (%) 1122/2992 (37.5) 766/1953 (39.2) 224/673 (33.3) .77 695/1714 (40.5) 108/295 (36.6) .08
Aneurysm location (%)
ACommA 879/2860 (30.7) 430/1452 (29.6) 290/811 (35.8) .002 620/1966 (31.5) 72/294 (24.5) .02
ACA 157/2860 (5.5) 109/1452 (7.5) 22/811 (2.7) ⬍.001 131/1966 (6.7) 11/294 (3.7) .05
MCA 663/2860 (23.2) 341/1452 (23.5) 219/811 (27.0) .006 512/1966 (26.0) 41/294 (13.9) ⬍.001
ICA 394/2860 (13.8) 246/1452 (16.9) 100/811 (12.3) ⬍.001 304/1966 (15.5) 19/294 (6.5) ⬍.001
PCommA 393/2860 (13.7) 156/1452 (10.7) 132/811 (16.3) ⬍.001 223/1966 (11.3) 55/294 (18.7) ⬍.001
Other anterior 76/2860 (2.7) 38/1452 (2.6) 16/811 (2.0) .22 42/1966 (2.1) 11/294 (3.7) .09
Basilar apex 142/2860 (5.0) 55/1452 (3.8) 23/811 (2.8) .21 52/1966 (2.6) 60/294 (20.4) ⬍.001
PCA 65/2860 (2.3) 53/1452 (3.7) 1/811 (0.1) ⬍.001 54/1966 (2.7) 2/294 (0.7) .04
Other posterior 91/2860 (3.2) 24/1452 (1.7) 8/811 (1.0) .18 28/1966 (1.4) 23/294 (7.8) ⬍.001
Hunt and Hess grade (%)
Grade I 301/1287 (23.4) 224/1009 (22.2) 77/278 (27.7) .06 239/809 (29.5) —
Grade II 328/1287 (25.5) 219/1009 (21.7) 109/278 (39.2) ⬍.001 274/809 (33.9) —
Grade III 329/1287 (25.6) 273/1009 (27.1) 56/278 (20.1) .02 195/809 (24.1) —
Grade IV 223/1287 (17.3) 198/1009 (19.6) 25/278 (9.0) ⬍.001 80/809 (9.9) —
Grade V 106/1287 (8.2) 95/1009 (9.4) 11/278 (4.0) .004 21/809 (2.6) —
Mean follow-up (months) 46.6 46.8 21.0 50.9 43.0
SAH, subarachnoid hemorrhage; AED, antiepileptic drug; ACommA, anterior communicating artery; ACA, anterior cerebral artery; MCA, middle cerebral artery; ICA, internal carotid artery;
PCommA, posterior communicating artery; PCA, posterior cerebral artery.

of patients analyzable for the AED prophy-
laxis cohort, AEDs were used in all 3232
cases, for a mean 4.1 months. The most
commonly used anticonvulsants were phe-
nytoin (82.6% of reported cases) and val-
proic acid (16.9% of reported cases). Ad-
verse events due to AED use were reported
in only 7 articles, and occurred in 21.4% of
cases (219 of 1025). The most common ad-
verse reactions were deranged liver func-
tion test (69 of 268 cases, 25.7%), thrombo-
cytopenia (21 of 268 cases, 7.8%), and rash
(5 of 362 cases, 7.8%). Stevens-Johnson
syndrome has been reported in 5 of 754
cases (0.7%). Switching or discontinuation
of AED was required in 112 of 815 reported
cases (13.7%).
Outcomes and Complications
Outcomes and complications of the whole
cohort, as well as cohorts of clipped vs.
coiled and AED prophylaxis vs. no AED pro-
phylaxis, are reported in Tables 3– 6.
Seizures. For the whole cohort, early (in-
hospital) seizures occurred in 121 patients
(2.3%). In the AED cohort, early seizures
were reported in 14 studies and occurred in
2.2% of patients (57 of 2610). In the no AED
cohort, early seizures were reported in 3
studies and occurred in 3.0% of patients (8
of 268). In the clipped cohort, early seizures
were reported in 10 studies and occurred in
2.4% of patients (67 of 2781). In the coiled
cohort, early seizures were reported in 3
studies and occurred in 1.4% of patients (17
of 1175). There was no significant differ-
ence in the incidence of early seizure in the
AED compared with the no AED cohort
(3.0% vs. 2.2%, P ⬎ .99), or between the
clipped compared with the coiled cohort
(2.4% vs. 1.4%, P ⫽ .16) (Figure 1).
For the whole cohort, late (after discharge)
seizures occurred in 386 patients (5.5%). The
mean time to seizures was 7.45 months. In
the AED cohort, late seizures were reported in
17 studies and occurred in 5.9% of patients
(190 of 3232) at a mean time to seizure of 5.6
months. In the no AED cohort, late seizures
were reported in 6 studies and occurred in
6.3% of patients (73 of 1165) at a mean time of
6.5 months. In the clipped cohort, late sei-
zures were reported in 10 studies and oc-
curred in 6.5% of patients (278 of 4281) at a
mean time of 5.9 months. In the coiled co-
hort, late seizures were reported in 4 studies
and occurred in 3.3% of patients (47 of 1418).
There was no significant difference in the
rates of late seizure between the AED and no
AED cohorts (5.9% vs. 6.3%, P ⬎ .99).
There was a higher rate of late seizure in the
clipped cohort compared with the coiled
cohort (6.5% vs. 3.3%, P ⬍ .003) (Figure 2).

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DANIEL M. S. RAPER ET AL. SEIZURES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE

Table 3. Seizure Outcomes in AED and No AED Patients in Aneurysmal SAH Studies
CEREBROVASCULAR

Total Cohort AED Cohort No AED Cohort

Number Occurrence/ P Value Number Occurrence/ P Value Number Occurrence/ P Value

of Total (All vs. of Total (AED vs. of Total (No AED
Studies Patients % AED) Studies Patients % No AED) Studies Patients % vs. All)

Presentation 14 277/4699 4.8 ⬍.003 10 158/1831 8.6 ⬍.003 3 0/268 0 ⬍.003

seizure
AED use 20 3244/4463 72.7 ⬍.003 17 3232/3232 100 ⬍.003 6 0/1165 0 ⬍.003
Time of AED 8.2 4.1 NA
exposure (months)
Early seizure 16 121/5191 2.3 ⬎.99 14 57/2610 2.2 ⬎.99 3 8/268 3.0 ⬎.99
Late seizure 25 386/7002 5.5 ⬎.99 17 190/3232 5.9 ⬎.99 6 73/1165 6.3 .82
Time to late 7.45 5.6 6.5
seizure (months)
AED, antiepileptic drug; SAH, subarachnoid hemorrhage; NA, not available.

Characteristics of Patients Who Experienced
Seizures. Among patients who experienced
seizures, aneurysms were located in the an-
terior communicating artery in 29.3%,
ACA in 6.5%, MCA in 39.0%, internal ca-
rotid artery in 13.8%, posterior communi-
cating artery in 8.9%, and basilar apex in
2.4% of cases. Patients who experienced
postoperative seizures had SAH grade I
in 25.0%, grade II in 18.3%, grade III in
41.7%, grade IV in 11.7%, and grade V in
3.3%. In the AED group, 33.3% of pa-
tients with seizures had anterior commu-
nicating artery aneurysms and 28.6% had
MCA aneurysms; 48.4% of patients were
HH grade III, whereas 32.3% were grade
I. In the no AED group, 41.7% of patients
had MCA aneurysms, whereas 29.8% had
ACommA aneurysms; 34.5% of patients
were HH grade III, with 27.6% being grade
II. In the clipped group, among patients
who experienced postprocedural seizures
47.9% of patients had MCA aneurysms,
whereas 21.1% had ACommA aneurysms;
48.4% of patients were HH grade III, and
32.3% were grade I. In the coiled group, the
location and SAH grade among patients
who experienced seizures was not reported.
There were no significant differences in
the location or grade of aneurysms among
patients experiencing postprocedural sei-
zures after aSAH between the clipped,
coiled, AED prophylaxis, and no AED pro-
phylaxis groups.
DISCUSSION
SAH has been associated with late seizures
both in studies of the condition’s natural
history and in series of treated patients
(9, 30, 32). Population-based data from pa-
tients treated in the 1950s and 1960s esti-
mated the 1- and 5-year incidence of epi-
lepsy after SAH at 18% and 25%,
respectively (40). In a Swedish review of ep-
ilepsy registry data, Adelow et al. found that
hospitalization for subarachnoid hemor-

Table 4. Seizure Outcomes in Clipped and Coiled Patients in Aneurysmal SAH Studies

Total Cohort Clipped Cohort Coiled Cohort

Number Occurrence/ P Value Number Occurrence/ P Value Number Occurrence/ P Value

of Total (All vs. of Total (Clip vs. of Total (Coil vs.
Studies Patients % Clip) Studies Patients % Coil) Studies Patients % All)

Presentation 14 277/4699 4.8 ⬎.99 9 140/2681 5.2 ⬍.003 4 39/1418 2.8 .003
seizure
AED use 20 3244/4463 72.7 .02 13 2020/2892 69.8 .006 1 26/52 50 ⬍.003
Time of AED 8.2 9.7 NR
exposure (months)
Early seizure 16 121/5191 2.3 ⬎.99 10 67/2781 2.4 .14 3 17/1175 1.4 .16
Late seizure 25 386/7002 5.5 .08 18 278/4281 6.5 ⬍.003 4 47/1418 3.3 ⬍.003
Time to late 7.45 5.9 NR
seizure (months)
SAH, subarachnoid hemorrhage; AED, antiepileptic drug; NR, not reported.

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DANIEL M. S. RAPER ET AL. SEIZURES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE

Table 5. Patient and Aneurysm Characteristics of Those Who Experienced Seizures with or without AED Prophylaxis

CEREBROVASCULAR
Total Cohort AED Cohort No AED Cohort

Number Occurrence/ P Value Number Occurrence/ P Value Number Occurrence/ P Value

of Total (All vs. of Total (AED vs. of Total (No AED
Studies Patients % AED) Studies Patients % No AED) Studies Patients % vs. All)

Aneurysm location
ACommA 8 36/123 29.3 ⬎.99 5 21/63 33.3 ⬎.99 5 25/84 29.8 ⬎.99
ACA 8 8/123 6.5 ⬎.99 5 5/63 7.9 ⬎.99 5 4/84 4.8 ⬎.99
MCA 8 48/123 39.0 .48 5 18/63 28.6 .31 5 35/84 41.7 ⬎.99
ICA 8 17/123 13.8 ⬎.99 5 10/63 15.9 ⬎.99 5 11/84 13.1 ⬎.99
PCommA 8 11/123 8.9 ⬎.99 5 7/63 11.1 ⬎.99 5 7/84 8.3 ⬎.99
Basilar apex 8 3/123 2.4 ⬎.99 5 2/63 3.2 ⬎.99 5 2/84 2.4 ⬎.99
SAH grade (Hunt and Hess)
Grade I 5 15/60 25.0 ⬎.99 4 10/31 32.3 .53 1 5/29 17.2 ⬎.99
Grade II 5 11/60 18.3 .84 4 3/31 9.7 .22 1 8/29 27.6 .95
Grade III 5 25/60 41.7 ⬎.99 4 15/31 48.4 .83 1 10/29 34.5 ⬎.99
Grade IV 5 7/60 11.7 ⬎.99 4 3/31 9.7 ⬎.99 1 4/29 13.8 ⬎.99
Grade V 5 2/60 3.3 .92 4 0/31 0 .41 1 2/29 6.9 ⬎.99
Intervention
Surgical clipping 12 283/347 81.6 9 151/154 98.1 5 67/70 95.7
Endovascular coiling 6 64/347 18.4 4 3/154 1.9 3 3/70 4.3
AED, antiepileptic drug; ACommA, anterior communicating artery; ACA, anterior cerebral artery; MCA, middle cerebral artery; ICA, internal carotid artery; PCommA, posterior communicating
artery; SAH, subarachnoid hemorrhage.

rhage was associated with an odds ratio of
5.1 (95% confidence interval: 1.1 to 23.0) for
subsequent unprovoked seizure (1). Sei-
zures have been associated with younger
age, MCA aneurysms, intracranial hemor-
rhage, and higher grade of SAH at presen-
tation (7, 10, 25, 27-29, 38, 39, 44, 46). Sub-
dural hematoma, cerebral infarction,
vasospasm, and hydrocephalus at presenta-
tion have been associated with risk of late
seizure in a prospective analysis (13, 18).
Seizure at presentation has not been found
to correlate with late seizures after aneu-
rysm repair in most studies (9, 18, 28, 54),
and these ictal events may be related to ab-
normal posturing (15), herniation, or raised
intracranial pressure rather than true sei-
zures (14, 17).
Previous work has suggested that most
seizures occur within the first year after re-
pair of ruptured intracranial aneurysms. In
one prospective cohort, 11% of patients
with SAH had at least 1 seizure within 12
months, with 7% experiencing 2 or more
seizures (13). In an older retrospective se-
ries, late seizures were reported in 14% of
patients at a mean latency of 8.4 months
(24). In our systematic analysis, late sei-
zures occurred at a mean of 7.45 months
from the time of initial hospitalization. Pa-
tients may continue to experience the onset
of seizures many years after the initial hos-
pitalization (43), however, which may most
commonly reflect rebleeding (46, 48). Late
seizures may also be related to gliosis, or to
the development of meningocerebral cica-
trix (17).
A recent survey of the Nationwide Inpa-
tient Sample database identified a 10% to
11% incidence of seizures or epilepsy after
clipping or coiling of ruptured intracranial
aneurysms (21). In the overall literature, a
number of studies utilizing different meth-
odologies and patient populations have re-
ported low seizure outcomes after aSAH (6,
7, 9, 16, 44). The publication of the ISAT
trial has resulted in significant shifts in
practice to incorporate greater numbers of
coiled patients because of the potential
morbidity and mortality benefits associated
with a minimally invasive procedure (2, 32).
Yet it is not clear whether coiling also en-
genders a lower risk of developing seizures
and epilepsy over the long term. Further-
more, the efficacy of prophylactic AEDs in
the prevention of early and late seizures re-
mains unquantified, and recent reviews
have reiterated the need for level 1 evidence
on the topic (26, 45).
The Effect of Clipping vs. Coiling on
Seizures
Late seizure rates of up to 26% have been re-
ported after aneurysmal SAH in patients treated
with surgical clipping (19). In coiled patients,
few studies have evaluated the late seizure risk,
butithasgenerallybeenfoundtobelower,inthe
range of 1.7% to 2.5% (9, 32). More recent stud-
ies of both treatment modalities report rates to-
ward the lower end of this range, and modern
neurosurgical strategies such as early surgery,
endovascular coiling, and dedicated neurologi-
cal critical care units may have contributed to
this observed decrease (47). Notably, studies re-
porting low rates of seizure after coil emboliza-
tion have had short follow-up—12 months in
the article by Claassen et al. (13), 12 months fol-

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 PEER-REVIEW REPORTS
DANIEL M. S. RAPER ET AL. SEIZURES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE

Table 6. Patient and Aneurysm Characteristics of Those Who Experienced Seizures After Clipping or Coiling
CEREBROVASCULAR

Total Cohort Clipped Cohort Coiled Cohort

Number of Occurrence/ P Value (All Number of Occurrence/ Number of Occurrence/

Studies Total Patients % vs. Clip) Studies Total Patients % Studies Total Patients %

Aneurysm location
ACommA 8 36/123 29.3 .21 5 15/71 21.1 NR
ACA 8 8/123 6.5 .39 5 7/71 9.9 NR
MCA 8 48/123 39.0 .22 5 34/71 47.9 NR
ICA 8 17/123 13.8 .83 5 9/71 12.7 NR
PCommA 8 11/123 8.9 .41 5 4/71 5.6 NR
Basilar apex 8 3/123 2.4 .87 5 2/71 2.8 NR
SAH grade (Hunt and Hess)
Grade I 5 15/60 25.0 .38 5 15/60 32.3 NR
Grade II 5 11/60 18.3 .28 5 3/31 9.7 NR
Grade III 5 25/60 41.7 .54 5 15/31 48.4 NR
Grade IV 5 7/60 11.7 .77 5 3/31 9.7 NR
Grade V 5 2/60 3.3 .31 5 0/31 0 NR
ACommA, anterior communicating artery; ACA, anterior cerebral artery; MCA, middle cerebral artery; ICA, internal carotid artery; PCommA, posterior communicating artery; SAH, subarachnoid
hemorrhage; NR, not reported.

low-upforthecompletecohortinISAT(32),and group (relative risk 0.52) (32). In a more recent atedwithahigherrateofepilepsy,thedifference

22 months in the Byrne et al. series of coiled
patients(9).Recentsurgicalseriesreportseizure
rates as low as 3% (11). It may be the case that, as
for other differences in outcomes between
clipped and coiled cohorts, as patients are fol-
lowed up for longer periods of time postinter-
vention for SAH, the significant differences be-
tween treatment modalities observed at 6 to 12
months diminish in size (31, 42).
Onlyalimitednumberofstudieshavedirectly
compared clipping and coiling to evaluate late
seizurerisk.IntheISATtrial,endovasculartreat-
ment was associated with a significantly lower
risk of seizure compared with the neurosurgery
analysis of the ISAT trial data, Scott et al. (49)
described neuropsychological outcomes
among ISAT patients from the UK. There was
no correlation between seizure at presentation
and cognitive impairment at 1 year, but there
was a higher incidence of late seizures in the
neurosurgical group than in the endovascular
group both for patients with cognitive impair-
ment (12 vs. 3) and without cognitive impair-
ment (6 vs. 4). Claassen et al. (13) prospectively
evaluated the rate of postoperative epilepsy in
247 patients with SAH to define predictors and
clinical impact of postoperative epilepsy, find-
ing that although surgical clipping was associ-
was not significant. These results are similar to
our own experience (43). However, in aggrega-
tion of the available published data, the inci-
dence of late (3.3% vs. 6.5%, P ⬍ .003) seizure
among coiled patients seems to be significantly
lower than among clipped patients. There was a
lower incidence of early seizures among the
coiledcohort(1.4%vs.2.4%),althoughthiswas
not significant. Some of the difference in late
seizures may be caused by surgical factors that
may contribute to a subsequent pro-seizure
state, including rebleeding, hyponatremia, de-
layed ischemic insult, or hydrocephalus (9, 36).

The Effect of AED Prophylaxis on

Figure 1. Incidence of early seizure among
patients treated for aneurysmal subarachnoid
hemorrhage, by cohort.
Figure 2. Incidence of late seizure among
patients treated for aneurysmal subarachnoid
hemorrhage, by cohort.
Seizures
Anticonvulsant drugs have been used to prevent
the incidence of postoperative seizures in aSAH
patients, but no clear consensus has been
reached regarding timing or efficacy of prophy-
lactic AEDs. AEDs have shown efficacy in pre-
venting seizures in traditional series of patients
undergoing craniotomy (14, 37). Most patients
who experienced late seizures in early studies
were not on AED prophylaxis at the time of their
seizure(46),implyingthatlong-termAEDsmay
have some beneficial effect. Two series have
demonstrated that restricting the timing of ad-
ministration of prophylactic AEDs to the imme-

688 www.SCIENCEDIRECT.com WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2012.08.006


DANIEL M. S. RAPER ET AL.
diate perioperative period does not increase the
incidence of postoperative seizures (3, 12). For a
population or subpopulation with a postopera-
tive seizure rate of 10% to 15%, AED prophylaxis
has been suggested as appropriate (14, 20).
However, in the modern literature there is lit-
tle evidence that AED prophylaxis is effective. A
number of retrospective series have demon-
strated no significant difference between
groups with or without prophylaxis in terms of
seizureoutcome(6,13,16,28,38).Inananalysis
of 4 large drug trials, Rosengart et al. (47) found
that patients who received AEDs had an odds
ratio of 1.56 for worse outcome at 3 months, as
well as increased risk for vasospasm, neurolog-
ical deterioration, cerebral infarction, and ele-
vated temperature during hospitalization. AED
use in this study was, however, associated with
younger age, worse neurological grade, and
lower systolic blood pressure at admission,
which likely contributed to the observed out-
comes in the AED cohort.
The adverse effects of AEDs have not been
well characterized in aSAH patients, but have
likely been underestimated. Phenytoin has been
associated with drug-induced fever and vaso-
spasm after aSAH (5), and adverse effects have
been reported in up to 35% of treated patients
(10, 22). In our review, among those receiving
AED prophylaxis, adverse effects due to medica-
tion were experienced in 21.4% of patients, re-
quiring switching in 13.7%, and included de-
ranged liver function test, thrombocytopenia,
rash, and Stevens-Johnson syndrome. In a pro-
spective study of 527 patients with SAH, higher
phenytoin burden was associated with poor
functionaloutcomeat14days,andworsecogni-
tive score at 3 months (33).
The potential for newer antiepileptic drugs
with reduced morbidity requires further investi-
gation. In 176 patients with aSAH initially
treated with phenytoin, 40% required replace-
ment with levetiracetam due to adverse events,
all of which resolved upon switching except
mental status and gastrointestinal disturbance
(50). In a recent prospective, randomized com-
parative trial in patients with traumatic brain in-
dustry or SAH, levetiracetam was associated
with better long-term outcomes and lower fre-
quency of worsened neurological status and
gastrointestinal upset than phenytoin (52).
Levetiracetam has been shown to be neuropro-
tectiveinamousemodelofSAH(55),incontrast
to phenytoin which was not associated with im-
proved functional or histological outcomes.
The argument from proponents of AED pro-
phylaxis is that it may be reasonable for patients
WORLD NEUROSURGERY 79 [5/6]: 682-690, MAY/JUNE 2013
SEIZURES AFTER ANEURYSMAL SUBARACHNOID HEMORRHAGE
with a high risk of seizure, such as those with
significantcorticalinjury,focalpathology,hem-
orrhage,orextensivesurgicalmanipulation(20,
35). However, there is no direct evidence to sup-
port this hypothesis. Despite the apparent in-
creased safety of newer antiepileptic agents,
even these drugs are associated with certain
morbidities such as fever, anemia, or cardiac ar-
rhythmias (52). It will be important for these
newer AEDs to demonstrate efficacy in the pre-
vention of seizures in the highest-risk patient
population to justify their use as prophylaxis.
Study limitations
The interpretation of our results is limited, in
part, by study heterogeneity, because investiga-
tions from multiple centers presented varying
study designs, methodologies, management
paradigms,adjuvanttherapies,andpatientpop-
ulations. A large proportion of the literature
evaluating surgical outcomes is subject to publi-
cation bias because it comprises single-center
experience (56).There was a significantly higher
incidence of presentation seizure among pa-
tients in the AED and in the clipped groups,
whichmayberelatedtoanincreasedriskofpoor
outcome, rebleeding, and late seizure (8,
40).The lack of a standardized protocol for the
use of AEDs raises the possibility of selection
bias. Indeed, use of AEDs varies by individual
neurosurgeons even within studies. Patients
deemed to be most at risk of developing seizure
may thus have preferentially been administered
prophylactic AEDs. Considering these limita-
tions, the objective of this review was not to pro-
vide level 1 evidence for the purposes of guiding
clinical practice, but to illustrate the usefulness
and limitations of AEDs as the evidence sup-
ports them in the modern literature.
CONCLUSIONS
Among patients with aSAH, the incidence of
early and late postoperative seizures is 2.3% and
5.5%,respectively.Theincidenceoflateseizures
among patients treated with endovascular coil
embolization seems to be lower than that
among patients treated with surgical clipping
(3.3% vs. 6.5%). Seizures after aneurysm oblit-
eration may occur at a considerable time after
initialhospitalizationandmanifestasavarietyof
seizuretypes.Nevertheless,thereseemstobeno
benefit to the administration of prophylactic
AEDs among aSAH patients. The routine use of
these drugs in patients with aneurysmal SAH
therefore cannot be supported by the available
evidence.
www.WORLDNEUROSURGERY.org
PEER-REVIEW REPORTS
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