Int J Clin Pharm

DOI 10.1007/s11096-017-0507-6

REVIEW ARTICLE

Levetiracetam versus phenytoin for seizure prophylaxis in brain

injured patients: a systematic review and meta-analysis
Anis Chaari1 • Alaa Sayed Mohamed1 • Karim Abdelhakim1 • Vipin Kauts1 •

William Francis Casey1

Received: 28 April 2017 / Accepted: 7 July 2017

 Springer International Publishing AG 2017

Abstract Background The onset of early and/or late sei-
zures in brain injured patients is associated with worse
outcome. So far, phenytoin is the most commonly used
antiepileptic drug to prevent seizures in this group of
patients. Objective In the current metaanalysis, we aimed to
compare the efficacy and safety of phenytoin versus leve-
tiracetam for seizure prophylaxis in brain injured patients.
Methods A systematic search was conducted in PubMed
and Cochrane Library Database by 2 investigators. Four
randomized controlled trials (RCTs) were included (295
patients). Data were extracted and the quality of each RCT
was assessed. Results Levetiracetam was found to be more
effective than phenytoin in seizure prophylaxis
(OR = 0.23; CI 95% [0.09–0.56]; Q test p value = 0.18
and I2 = 38%). A trend toward less serious side effects was
also found in patients treated with levetiracetam
(OR = 0.27; CI 95% [0.07–1.07]; Q test p value = 0.72
and I2 = 0%). Conclusion Levetiracetam is more effective
and safer than phenytoin for seizure prophylaxis in brain
injured patients.
Keywords Efficacy
Levetiracetam
Phenytoin,
Prophylaxis
Side effects
Seizure
& Anis Chaari
anischaari2004@yahoo.fr
1 reported [10, 11]. Therefore, a particular interest was given
King Hamad University Hospital, Muharraq, Bahrain
Impacts on practice
• Levetiracetam is a useful option to prevent seizures in
brain-injured patients. Overall, it is more effective than
phenytoin in this regards.
• Levetiracetam is at least as safe as phenytoin.
Introduction
Seizures are common in brain injured patients and are usu-
ally associated with poor outcome [1, 2]. In fact, epileptic
seizures were diagnosed in up to one third of comatose
patients with traumatic, anoxic or vascular brain insults and
were responsible of delayed regain of the conscious level
[3]. Further studies including homogeneous groups of
patients reported similar findings. In fact, stroke patients
with early and/or late seizures were found to have higher
admission rate to intensive care units and higher mortality
[4]. Similarly, seizures significantly affect the functional
outcome in patients with traumatic brain injury [5, 6]. Even
though preventing the occurrence and the recurrence of this
condition in brain injured patient may improve their prog-
nosis, significant discrepancy regarding the indication, the
modalities and the duration of the antiepileptic prophylaxis
are still noticed, mainly because of the lack of well designed
randomized controlled trials (RCTs) [7, 8]. Moreover, only
few drugs were tested to prevent seizures in brain injured
patients. Phenytoin (PHEN) was one of these few drugs and
studies showed controversial results regarding its effective-
ness and the prognostic impact of its side effects [9]. In fact,
serious side effects such as purple glove syndrome, drug–
drug interaction, hypotension and cardiac arrhythmias were

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to new anti-epileptic drugs—mainly Levetiracetam (LEV)— seizures are those occurring beyond this time frame [12].
as they were reported to be safer and at least as effective as Side effects were considered as serious whenever they are
Phenytoin. However, whether levetiracetam is effective to leading to treatment discontinuation.
prevent seizures in brain injured patients is still The quality of each RCT was assessed by the calculation
questionable. of JADAD score varying from 0 to 5 (0 the worst—5 the
The aim of the current meta-analysis is to compare the best) [13].
effectiveness and safety of Phenytoin Versus Levetirac-
etam in preventing early and/or late onset seizures in brain-
Statistical analysis
injured patients.
Two therapeutic interventions aiming for seizure prophy-
laxis in brain injured patients were compared: Levetirac-
Materials and methods
etam versus Phenytoin. The primary outcome was the
occurrence of early or late seizure after starting the
Search strategy
antiepileptic drugs. The secondary outcome was the
occurrence of any serious adverse effect leading to treat-
Two investigators (AC and AM) performed a systematic
ment discontinuation. The statistical analysis was per-
search of the relevant studies published between 01/01/
formed according to the Mantel Haenszel model to
1985 and 30/09/2016 in PubMed and Cochrane Library
calculate Odds ratios with corresponding 95% confidence
Database. The following MeSH terms were used with
intervals (CIs). A 0.5 continuity correction was performed
different Boolean connectors’ combinations (AND/OR):
whenever a zero value was present. Statistical hetero-
Etiracetam, Phenytoin, seizure, brain injuries, stroke, head
geneity of the included studies was assessed by the
injuries, brain neoplasms and subarachnoid hemorrhage.
Cochrane Q test and I2 [14]. A p value \ 0.1 was consid-
Only studies published in English and including adult
ered as statistically significant. An I2 [ 50% was consid-
patients were considered for further assessment.
ered as synonym of significant heterogeneity. Accordingly,
a pooled summary effect was computed based on fixed-
Study selection
effect model or random-effect model as appropriate. For-
rest plots and funnel plot were generated. The statistical
Both investigators independently reviewed the titles,
analysis was performed by using the RevMan 5.3 software
abstracts and references of all the articles. Inclusion criteria
according to the Cochrane Collaboration and the Quality of
were the following: (1) Population: Adult patients with
Reporting of metaanalysis recommendations [15].
brain injury (head trauma, ischemic or hemorrhagic stroke,
brain neoplasm or subarachnoid hemorrhage). (2) Inter-
vention: included patients received either Levetiracetam or
Phenytoin for seizure prophylaxis. (3) Design: Randomized 95 articles in the initial search
controlled trial. (4) Outcome: Incidence of early or late
seizures—Occurrence of serious adverse effect. 83 articles excluded after
We excluded from the current metaanalysis: (1) retro- the initial screening
spective studies. (2) Prospective, non-controlled studies.
(3) Studies comparing (PHEN) and (LEV) given to treat
12 studies selected for critical
seizures. (4) Studies including patients receiving either screening
(PHEN) or (LEV) combined with other antiepileptic 8 Excluded studies:
drugs.
- 1: Combination with other AED.

Data extraction and study characteristics - 2: Curative use of LEV or PHEN

- Non randomized trials: 4

For each study, we recorded the design, the cause of brain - Experimental study: 1
injury, and the modality treatment for each drug (dose,
route, and duration). The included studies should also
include the required information regarding the outcomes:
4 included randomized controlled
(1) the occurrence of any early or late seizure and (2) the trials
occurrence of any serious adverse effect.
Early seizures were defined as seizures occurring during Fig. 1 Flowchart of the meta-analysis. AED antiepileptic drugs, LEV
the first week following the brain insult whereas late Levetiracetam, PHEN Phenytoin

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Table 1 Characteristics of the randomized controlled trials included in the meta-analysis

Trial Number Patient JADAD Protocol Duration of Early/late Serious side
of population score the seizures (n) effects (n)
patients treatment
LEV PHEN LEV PHEN

Fuller 74 Post- 5 LEV 250–1000 mg daily (At least one dose C3 days 0 6 1 2
et al. craniotomy IV)
[18] PHEN 300 to 1000 mg IV and then 300 mg
daily (Serul level follow-up)
Lim et al. 23 Glioma/post 2 All included patients were on PHEN before Follow up 2 2 0 0
[17] craniotomy surgery. After randomization: for
LEV 1000 mg Bid ? tapering PHEN over 6 months
3 days
PHEN Continue the same regimen ? serum
level follow-up
Szaflarski 52 TBI/SAH 5 LEV 20 mg/kg (IV) (Loading) and then 7 days 5 3 N/A N/A
et al. 1000 mg twice daily (max: 1500 mg twice
[19] daily)
Fos-PHEN 20 mg/kg (IV) (loading) and then
5 mg/kg daily (serum level follow-up)
Iuchi 146 Brain 3 Fos-PHENLEV 500 mg after 7 days 1 11 0 5
et al. tumor/post induction ? 500 mg twice daily during
[16] craniotomy 7 days
Fos-PHEN 15–18 mg/kg after
induction ? 5–7.5 mg/kg daily (IV) and
then 250 mg (PO) daily
PHEN Phenytoin, LEV: Levetiracetam, Bid Twice daily, TBI Traumatic brain injury, SAH Subarachnoid Hemorrhage; N/A not available

Results incidence in brain injured patients (OR = 0.23; CI 95%

Study characteristics
Ninety five studies were identified after the initial search.
Only 12 studies were considered for potential inclusion and
were thoroughly reviewed whereas 83 were excluded.
Ultimately, 4 studies (295 patients) were included in the
metaanalysis (Fig. 1). The cause of brain insult was cere-
bral tumors in two studies [16, 17] whereas it was more
heterogeneous for the two other studies [18, 19]. Cran-
iotomy was performed for all the patients included in three
studies [16–18] (Table 1).
Study validity and data quality
[0.09–0.56]). There was no significant heterogeneity
between the included studies as Cochrane Q test p value
was 0.18 and I2 was 38%. The assessment of the studies
heterogeneity by funnel plot analysis is shown in (Fig. 2).
Serious adverse events
Pooled studies analysis showed a trend toward less serious
adverse events in patients treated with levetiracetam
(OR = 0.27; CI 95% [0.07–1.07]). There was no signifi-
cant heterogeneity between the included studies (Cochrane
Q test p value = 0.72 and I2 = 0%). The assessment of the
studies heterogeneity by funnel plot analysis is shown in
(Fig. 3).

All the included studies were randomized controlled trials.

JADAD score range was from 2 to 5. Data regarding the
main outcome (seizure prophylaxis) were extracted from
all the included studies [16–19] whereas data regarding the
serious adverse events were available in only three studies
[16–18] (Table 1).
Effectiveness for seizure prophylaxis
After pooling the data of all included studies, levetiracetam
use was significantly associated with decreased seizure
Discussion
The current metaanalysis shows that levetiracetam is more
effective than Phenytoin to prevent seizure in brain injured
patients. It also shows a trend toward decreased incidence
of serious side effects with levetiracetam. A previous
metaanalysis comparing both drugs yielded to different
findings [12]. In fact, Zafar et al. [12] reported that leve-
tiracetam and Phenytoin have similar efficacy in preventing
seizure prophylaxis. However, only two RCTs with limited

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Fig. 2 a Forrest plot Phenytoin Versus Levetiracetam for seizure
prophylaxis. Weight if the relative contribution of each study to
overall estimate the treatment effect estimating a fixed-effect model.
sample size were included in the metaanalysis and signif-
icant heterogeneity among the studies has been reported.
The concept of seizure prophylaxis relies on the results of
previous studies showing that the onset of epileptic activity
following brain injury is associated with increased mortality
and worse functional outcome [20–22]. Moreover, previous
studies showed that up to 21% of critically-ill brain injured
patients present non convulsive seizures on continuous
electroencephalogram monitoring [23, 24]. Therefore, pre-
venting this complication might be indicated especially that
such monitoring is not available in most of the intensive care
units. Phenytoin is one of the antiepileptic drugs that were
extensively studied in seizure prophylaxis. In fact, Temkin
et al. [25] reported that Phenytoin significantly decreased
the incidence of early seizures in patients with traumatic
brain injury. However, available data regarding the effec-
tiveness of phenytoin in patients with other underlying
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Int J Clin Pharm
b Funnel plot Phenytoin Versus Levetiracetam for seizure prophy-
laxis. Each point represent one trial
causes of brain injury are less conclusive [26]. In fact, sei-
zure prophylaxis with phenytoin in patient with hemor-
rhagic stroke has been reported to be associated with worse
functional outcome [27]. Similar results were reported in
patients with subarachnoid hemorrhage as phenytoin use
was associated with worse cognitive status, especially if the
drug is given for a long period of time [28–30]. Beside the
controversies regarding the efficacy of phenytoin, concerns
has been raised regarding the associated serious side effects
such as arrhythmias, severe skin hypersensitivity reaction
and drug–drug interaction through the induction of the
hepatic cytochrome P450 system [31]. Close monitoring of
phenytoin serum level is also required because of its slow
clearance and non linear pharmacokinetics [32]. In
hypoalbuminemic patients, the free phenytoin level should
be checked as more than 90% of phenytoin is bound to
albumin [32, 33].
Int J Clin Pharm
Fig. 3 a Serious side effects Forrest plot of pooled analysis of included. b Funnel plot Phenytoin Versus Levetiracetam for serious side effects.
Each point represent one trial
For all these reasons, new antiepileptic drugs, such as
levetiracetam, has been increasingly used as an alternative
option for seizure prophylaxis in brain injured patients.
Levetiracetam acts by binding to the synaptic vesicle
protein A leading to neurotransmitter release modulation
[34]. Our metaanalysis shows that levetiracetam is more
effective than phenytoin. This finding can be related to
different mechanism of action, better pharmacokinetic
stability as levetiracetam is only 10% albumin bound and
less adverse events leading to treatment discontinuation
[35, 36]. Moreover, it shows a trend toward decreased
serious side effects with levetiracetam which makes it an
attractive option for seizure prophylaxis [37]. However,
our findings should be taken with caution for several rea-
sons: First, most of the included patients had craniotomy as
part of their management. Whether the subgroup of
patients who did not require such surgical intervention
would get more benefit from levetiracetam than from
phenytoin in seizure prophylaxis need to be investigated.
Second, we included patients with different underlying
diseases. Subgroup analysis was not considered because of
the limited sample size of most of the included studies.
Third, the dosing regimen of levetiracetam was variable in
one of the studies included in the current metaanalysis
[18]. Finally, the impact of seizure prophylaxis on mor-
tality and functional outcome was not assessed because of
lacking data.
Conclusion
Levetiracetam is more effective than phenytoin for seizure
prophylaxis in brain injured patients. Serious side effects
are more likely to occur with phenytoin rather than leve-
tiracetam. More RCTs including more homogeneous
patients are needed to confirm our findings.
Conflicts of interest None.
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