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MANAGEMENT UPDATE

Antiepileptic Drugs in
Aneurysmal Subarachnoid
Hemorrhage
Alexander Y. Zubkov, MD, PhD, Eelco F.M. Wijdicks, MD, PhD
Division of Critical Care Neurology, Mayo Clinic, and Neurology/Neurosurgery Intensive Care Unit,
Saint Marys Hospital, Rochester, MN

Seizures may occur during or soon after rupture of an intracranial aneurysm. The use
of antiepileptic drugs (AEDs) is a controversial issue. The overall conclusions from 2 re-
cent studies in aneurysmal subarachnoid hemorrhage are that 1) many patients receive
AEDs but should not; 2) long-term use is associated with worse outcome; and 3) short-
term use is safer. Phenytoin may not be the first choice for seizure prophylaxis; newer
AEDs such as levetiracetam might be more helpful in prevention and treatment of
seizures.
[Rev Neurol Dis. 2008;5(4):178-181]
© 2008 MedReviews®, LLC

Key words: Antiepileptic drugs • Seizures • Subarachnoid hemorrhage • Toxicity

S
eizures may occur during or soon after rupture of an intracranial aneurysm,
causing subarachnoid hemorrhage (SAH).1 Seizures may have a detrimen-
tal effect by increasing intracranial pressure, causing aspiration, and in-
creasing blood pressure to unsafe levels in an unsecured aneurysm. The pro-
phylactic use of antiepileptic drugs (AEDs) in patients with SAH was
recommended after early studies suggested a 20% to 30% incidence of seizures,
related mostly to initial hemorrhage or rebleeding from the aneurysm.2

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Current Evidence
Seizures at the onset of SAH are inde-
pendently related to poor out-
come,3,4 although this is not a uni-
versally accepted concept; there are
some who suggest that seizures
merely reflect the severity of brain
injury.5
Two recent studies address pro-
phylactic use of AEDs in SAH. In the
first study, Chumnanvej and col-
leagues6 evaluated the effects of a 3-
day course of phenytoin compared
with their historical experience with
prolonged AED prophylaxis (ie, drug
coverage during the entire hospital-
ization) on the incidence of seizures.
In the prolonged treatment group
(group 1), 79 patients were included
and treated with phenytoin from ad-
mission to discharge. For the 3-day
course group (group 2), 374 patients
were included in the study. Both
groups received a loading dose of
phenytoin, 1000 mg, followed by
100 mg 3 times daily. Aneurysms
were repaired within 3 days in 95%
of the patients, with a majority of
the patients treated with surgical
clipping.
Drug hypersensitivity reaction
was documented in 8.8% of those
in group 1 and in 0.5% of those in
group 2. In addition, phenytoin was
considered the cause of central
fever in 23 patients from group 1.
The incidence of seizures (much
lower than the usually cited 10%)
did not differ significantly between
groups (1.3% vs 1.9%, group 1 vs
group 2; P  .603). Over the long
term, 5.7% of patients in group 1
developed seizures as compared
with 4.6% of patients in group 2
(P  .573). The mortality and
length of stay did not differ statisti-
cally between groups. This study
has important clinical implications.
It does not answer the more com-
pelling question of whether AEDs
are needed in the first place; how-
Antiepileptic Drugs in Aneurysmal Subarachnoid Hemorrhage
Table 1
Rates of Seizure and Hypersensitivity Reaction in 2 Treatment Periods
July 1998–March 1999 April 1999–June 2002
Patients (n) 79 370
Phentoin hypersensitivity 7/79 (8.8%) 2/370 (0.5%)
Seizures during hospitalization 1/79 (1.3%) 7/370 (1.9%)
Seizures at follow-up (survivors only) 3/53 (5.7%) 12/261 (4.6%)
Hospital length of stay (d) 14.2 13.1
Reprinted with permission from Chumnanvej S et al. 6
ever, it shows a fairly safe profile for treated with AEDs had a higher rate
phenytoin use when taken for only of unfavorable Glasgow Outcome
a few days and until the aneurysm Scale (GOS) scores compared with pa-
is secured (Table 1). tients not treated with AEDs, even
The second study, by Rosengart after adjustment for study center,
and coworkers,7 used the tirilazad WFNS grade, age, and systolic blood
trial database, which included 3552 pressure on admission. The detri-
patients with aneurysmal SAH. The mental effect of AEDs was demon-
use and choice of AEDs varied con- strated at 3-month outcome regard-
siderably. A total of 64% of patients less of WFNS grade. The incidence of
had at least 1 prescription for an all in-hospital complications was
AED. Phenytoin was used most fre- higher in AED-treated patients.
quently (52.8%), followed by pheno-
barbital (18.7%) (Figure 1). Assessment of Data
There was a significant linear trend The overall conclusions from those 2
for worsening World Federation of papers, which mainly assessed older
Neurosurgical Societies (WFNS) grade AEDs in aneurysmal SAH, are that 1)
with increasing use of AEDs. Patients many patients receive AEDs when
Denmark (n  121)
Sweden (n  332)
Germany (n  337)
Canada (n  434)
Australia (n  243)
United States (n  1277)
Italy (n  338)
0 20 40 60 80 100
Prevalence of Anticonvulsant Use (%)
Figure 1. Bar graph showing the prevalence rate of antiepileptic drug use in patients with subarachnoid hemor-
rhage in study countries with more than 100 patients enrolled. Reprinted with permission from Rosengart AJ et al.7
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Antiepileptic Drugs in Aneurysmal Subarachnoid Hemorrhage continued

they should not; 2) long-term use is
associated with worse outcome; and
3) short-term use is safer.
Phenytoin toxicity was suggested
both in experimental and clinical ob-
servations. Phenytoin might impair
recovery from brain injury in animal
One of the mechanisms of action of AEDs is to reduce neuronal irritability,
which may result in altered synaptic growth and connectivity, which in turn
may be important in neurological recovery.
models8 and also worsens cerebral
ischemia in patients.9 The study per-
formed specifically in the patients
with SAH demonstrated that higher
phenytoin burden (defined as average
serum phenytoin level multiplied by
the time in days between the first and
last measurement) increased the odds
of poor outcome by 1.5 per quartile.10
In addition, the same study demon-
strated that a higher quartile of
phenytoin burden was associated
with worse performance on cognitive
tests even after correction for Hunt-
Hess grade at hospital admission.10
The mechanism for neuronal in-
jury is highly unclear at this point.
One of the mechanisms of action of
AEDs is to reduce neuronal irritabil-
ity, which may result in altered
synaptic growth and connectivity,
which in turn may be important in
neurological recovery.11 Many AEDs
block glutamate-mediated excitation
and are known to cause widespread
and dose-dependent apoptotic neu-
rogeneration in the developing rat
brain.12 In humans, phenytoin might
cause fever, which in itself is strongly
associated with poor outcome and
increased length of hospitalization.13
There are some preliminary data showing that levetiracetam might have
neuroprotective effects in animal models of closed head injury and sub-
arachnoid hemorrhage.
Fever in patients with SAH is asso-
ciated with poor outcome after
correction for other prognostic vari-
ables14; thus, phenytoin should not
be the first choice for seizure pro-
phylaxis. Newer AEDs might be
more helpful in prevention and
treatment of seizures. The main
problems with newer medications
are that most of them are not avail-
able in intravenous form, the thera-
peutic levels of the medication are
not well established, and they are
hard to monitor.
One medication that has been
recently approved for intravenous
use is levetiracetam. There are
some preliminary data showing
that levetiracetam might have neu-
roprotective effects in animal
models of closed head injury and
SAH.15 No data are currently avail-
able on the effects of leve-
tiracetam in patients with SAH, or
whether it is safe and effective to
prevent and control seizures in this
population.
Conclusions
Do we need to use AEDs in patients
with SAH? It is hard to justify in alert
patients at low risk. Stuporous pa-
tients in a poor-grade SAH may have
subtle seizures and electroencephalo-
graphic monitoring may be helpful
in making the decision to proceed
with AED treatment.

Main Points
• Seizures may occur during or soon after rupture of an intracranial aneurysm, causing subarachnoid hemorrhage (SAH)
and other serious deleterious effects.
• The prophylactic use of antiepileptic drugs (AEDs) in patients with SAH was recommended, although their use is
controversial.
• The overall conclusions of 2 recent studies are that 1) many patients receive AEDs when they should not; 2) long-term
use is associated with worse outcome; and 3) short-term use is safer.
• Phenytoin should not be the first choice for seizure prophylaxis; however, early studies are showing that levetiracetam
may have neuroprotective effects in animal models of closed head injury and SAH.
• Electroencephalographic monitoring may be helpful in making the decision to proceed with AED treatment in pa-
tients with SAH.

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