Journal of Clinical Neuroscience 22 (2015) 959963

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Clinical Study

Levetiracetam versus phenytoin in management of status epilepticus

Sudheer Chakravarthi, Manoj Kumar Goyal, Manish Modi , Ashish Bhalla, Parampreet Singh
Department of Neurology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India

a r t i c l e

i n f o

Article history:
Received 2 August 2014
Accepted 14 December 2014

Keywords:
Levetiracetam
Phenytoin
Randomized trial
Seizures
Status epilepticus

a b s t r a c t
The purpose of this study was to compare safety and efcacy of intravenous (IV) levetiracetam (LEV) with
IV phenytoin (PHT) in management of status epilepticus (SE). The second-line treatment of SE is limited
to a few drugs available in an IV formulation such as PHT, fosphenytoin and valproate. The relative lack of
serious side effects and favourable pharmacokinetics of LEV made it a promising option in management
of SE. Randomized trials comparing relative efcacy of second-line agents are remarkably lacking. In this
study, consecutive patients of SE (n = 44) were randomized to receive either IV PHT (20 mg/kg) or IV LEV
(20 mg/kg). The primary end point was successful clinical termination of seizure activity within 30 min
after the beginning of the drug infusion. Secondary end points included recurrence of seizures within
24 hours, drug related adverse effects, neurological outcome at discharge, need for ventilatory assistance,
and mortality during hospitalization. Both LEV and PHT were equally effective with regard to primary and
secondary outcome measures. PHT achieved control of SE in 15 (68.2%) patients compared to LEV in 13
(59.1%; p = 0.53). Both the groups showed comparable results with respect to recurrence of seizures
within 24 hours (p = 0.34), outcome at discharge as assessed by functional independence measure
(p = 0.68), need of ventilatory assistance (p = 0.47) and death (p = 1). From this study it can be concluded
that LEV may be an attractive and effective alternative to PHT in management of SE.
2015 Elsevier Ltd. All rights reserved.

1. Introduction
Status epilepticus (SE) is a common neurological emergency
with mortality rates ranging from 339% across different studies.
Generalized tonic clonic status epilepticus (GCSE) represents
the most severe form of SE with high mortality and morbidity
[1,2]. The annual incidence of SE in studies from Virginia and
Minnesota, USA, was 135155 per 100,000 in patients less than
1 year of age and 6386 per 100,000 in patients older than 60 years
[1]. About 1025% of all children and 5% of all adults with epilepsy
will have at least one episode of SE during their lifetime [3,4].
In view of high mortality and morbidity it is imperative that SE
be treated promptly. However, despite more than 150 years of
research, treatment of SE remains controversial and is largely
based on empirical recommendations rather than well conducted
clinical studies. Currently, high level evidence is available only
for the rst-line medications of SE which includes intravenous
(IV) benzodiapines [5,6]. Since rst-line therapy fails to control at
least 3545% of the time, additional treatment is necessary for
most patients [7]. Some of the conventional agents being used as
second-line treatment include phenytoin (PHT), fosphenytoin and
Corresponding author. Tel.: +91 9876197533.
E-mail address: modim72@yahoo.com (M. Modi).
http://dx.doi.org/10.1016/j.jocn.2014.12.013
0967-5868/ 2015 Elsevier Ltd. All rights reserved.

valproate. However, use of these drugs is limited by their toxicity

(lorazepam: hypotension and respiratory suppression; phenytoin:
hypotension, purple glove syndrome and cardiac toxicity) [8,9].
Therefore, there is a need for newer, more effective and less toxic
drugs for management of SE. More recently, levetiracetam (LEV)
has also been ascribed to treatment of SE but there is still a lack
of well-designed clinical trials supporting its efcacy in SE [10].
LEV was rst introduced in 1999 and its use has rapidly spread
due to its pharmacological properties (minimal protein-binding
and drugdrug interactions) and a favourable side effect prole
[11]. Unlike many other anticonvulsant drugs, it is not extensively
metabolized in the liver by the cytochrome P450 enzyme system
and is primarily excreted through the kidneys. In addition, drug
level monitoring is not required for LEV owing to its linear and
more predictable pharmacokinetics. Its mechanism of action is also
unique as it binds to synaptic vesicle protein SV2A and enhances
neurotransmission by increasing the available amount of secretory
vesicles and, therefore, probability of their release [12,13]. LEV is
already known to be safe and efcacious in management of seizures and is also being increasingly used in management of SE
[1416]. However, its use in SE is based largely on experience from
case reports and small case series [17] and there is a remarkable
lack of prospective studies or randomized trials supporting LEV
for SE. Hence, we designed this randomized open label study to

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S. Chakravarthi et al. / Journal of Clinical Neuroscience 22 (2015) 959963

determine the role of LEV as an alternative to PHT and compare

efcacy and safety in treatment of SE.

3. Results
3.1. Patient demographics

2. Methods
2.1. Patient criteria and treatment
The current study comprised 44 patients who were admitted to
the emergency medical or neurology ward of our tertiary care hospital in Northern India. The study period was between July 2012
and December 2013. Consecutive patients presenting with SE were
enrolled in the study after obtaining informed consent. As most of
the patients were in altered sensorium, written informed consent
was obtained from the rst degree relatives of patients before
inclusion in the study. Randomization was done using a simple
random sampling method in which the patients were assigned to
either LEV or PHT depending on the order of recruitment into the
study. Odd numbered patients received PHT (n = 22; group A)
and those with even numbers were administered LEV (n = 22;
group B). SE was dened as continuous, generalized, convulsive
seizure lasting >5 min, or two or more seizures during which the
patient does not regain normal sensorium [18].
All patients received a bolus injection of IV lorazepam 0.1 mg/kg
at 1 mg/minute. Subjects were enrolled into the study if seizures
were uncontrolled with lorazepam. Seizures were controlled with
lorazepam alone in 76/120 (63.3%) patients. Patients whose
seizures were terminated with lorazepam were excluded from
the study. Patients of group A received IV PHT at a dose of
20 mg/kg (maximum rate 50 mg/min) after dilution with normal
saline and patients in group B received IV LEV at a dose of
20 mg/kg as loading dose (rate 100 mg/min). This was followed
by maintenance doses of the respective drug.
Inclusion criteria for the study were patients who fullled the
denition of SE and failed to improve with IV lorazepam, and
where written consent for participation in the study was obtained.
Exclusion criteria for the study were patients who were already
taking the study drug, patients who had a prior history of allergy to
the study drugs and those with drug withdrawal seizures.
Detailed history was taken and meticulous general physical,
systemic and neurological examinations were performed. All
patients underwent relevant investigations for determination of
the etiology of SE. Neuroimaging was done for all and scalp electroencephalography (EEG) was carried out in 75% of the patients.
Additional antiepileptic drugs were administered in cases
where seizures were uncontrolled or recurred within 24 hours of
treatment.
2.2. End points
The primary end point was successful clinical termination of
seizure activity within 30 min after initiation of drug infusion.
The secondary end points included recurrence of seizures within
24 hours after control of SE, drug related adverse effects, neurological outcome at discharge as assessed by functional independence
measure (FIM; good outcome if FIM score of 57, poor if 14), need
for ventilatory assistance, and mortality during hospitalization.
2.3. Statistical analyses
The two groups were characterized using descriptive statistics.
Comparisons between the groups were done using Fishers exact
test for categorical variables and the MannWhitney U-test for
continuous variables. Generalized linear models were used to test
for differences between groups adjusted for confounding factors.
Statistical analyses were conducted using SPSS Statistics (version
22, IBM Corporation, Armonk, NY, USA).

This prospective study comprised 44 patients with SE. Fortyone had GCSE and three had focal convulsive status epilepticus
(FCSE). The mean age of patients was 35.41 a standard deviation
(SD) of 16.03 years (range: 1475). The study group included 25
men and 19 women. The mean duration of status was 63.98 SD
78.32 min and median (interquartile range; IQR) of 30.0 min
(range: 20.060.0) min. Among the patients who responded well
to treatment, the duration of SE was 35.9 SD 28.9 min (median
IQR of 30 min [range: 16.2560]) while among the non-responders
it was 113.13 SD 109.6 min (median IQR of 60 min [30165]).
Past history of epilepsy was noted in 31 (70.4%) patients.
3.2. Comparison between group A and B
The results of the following comparisons are summarized in
Table 1.
The patients were divided into two groups. Group A received
PHT (n = 22) and group B received LEV (n = 22). Mean age of
patients was 31.82 SD 12.68 years in group A and 39.00 SD
18.40 years in group B. Mean duration of hospital stay was
1.57 SD 1.36 days in group A and 1.82 SD 1.29 days in group
B. Mean duration of SE was 72.05 SD 48.57 min in group A and
55.91 73.75 min in group B. Among the patients who responded
well to treatment in group A, duration of SE was 35.7 31.7 min
(median: 30) while among the non-responders it was 120 108
min (median: 60). Among the patients who responded well to
treatment in group B, duration of SE was 37.9 26.5 min (median:
30) while among the non-responders it was 114.4 107.9 min
(median: 60). Past history of epilepsy was reported in 66.6% of
group A and in 77.3% of group B. In group A, 21 patients had
GCSE and one had FCSE while in group B 20 had GCSE and two
had FCSE. These parameters were comparable between the two
groups. Past history of SE was noted in only two (4.5%) patients.
3.2.1. Etiology of SE
SE patients were divided into three types based on etiology.
These were remote symptomatic (n = 13, 29.5%), acute symptomatic (neurocysticercosis, tuberculomas, viral encephalitis, cerebral venous sinus thrombosis, hypocalcemia; n = 18, 41%) and
idiopathic (n = 13, 29.5%). Both groups were comparable in terms
of these etiologies.
3.2.2. Laboratory parameters
Laboratory parameters (hemoglobin, total and differential leucocyte counts, platelet counts, blood glucose, renal and liver function tests, serum electrolytes, calcium, phosphorus and
magnesium, cerebrospinal uid analysis) showed abnormal results
with respect to leucocytosis (31.8%), hypocalcaemia (13.6%) and
hypomagnesemia (2.3%). Comparison of these parameters within
the two groups showed that both groups were comparable.
3.2.3. SE severity score (STESS)
STESS [19] is used to predict the outcome of SE. Both groups
were comparable in terms of STESS score.
3.2.4. Neuroimaging ndings
Neuroimaging (contrast enhanced CT scan of the brain and/or
brain MRI) was done in all the patients. Contrast enhanced CT scan
was carried out in 39 (81.81%), MRI brain in 26 (59.1%) and 21
(47.7%) patients underwent both. Neuroimaging (brain CT scan or
MRI) was abnormal in 31 (70.5%) patients. Neurocysticercosis

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S. Chakravarthi et al. / Journal of Clinical Neuroscience 22 (2015) 959963

Table 1
Comparison of various parameters between SE patients treated with PHT or LEV
Parameter

Group A PHT (n = 22)

Group B LEV (n = 22)

p value

39.00 18.40
55.91 73.75
GCSE, 20
Focal, 2
M, 12
F, 10
17

0.140
0.501
1.0

Positive past history of seizures

31.82 12.68
72.05 48.57
GCSE, 21
Focal, 1
M, 15
F, 7
14

Etiology of SE
Idiopathic
Acute symptomatic
Remote symptomatic

7
3
12

6
10
6

0.53

Laboratory parameters
Hypocalcemia
Leucocytosis

5
7

1
7

0.18
1

STESS
0
1
2
3
4
Neuroimaging abnormality

2
9
4
7
0
15

2
10
5
3
2
16

0.51

Type of abnormality on neuroimaging

Normal
Calcied granuloma
Neurocysticercosis
Chronic infarct
Gliotic scar
Viral encephalitis
Cerebral venous sinus thrombosis
Hypoparathyroidism
Tuberculoma
Focal cortical dysplasia

8
0
7
1
2
1
1
1
1
0

6
1
4
3
5
1
0
0
1
1

0.68

Age (years)
Duration of SE* (min)
Type of SE, n
Sex, n

0.128
0.322

0.74

F = female, GCSE = generalized convulsive status epilepticus, LEV = levetiracetam, M = male, PHT = phenytoin, SE = status epilepticus, STESS = SE severity score.
Figures are reported as the mean standard deviation.

was the leading cause of SE followed by gliotic scar. Other causes

included infarcts, cerebral venous sinus thrombosis, hypoparathyroidism and focal cortical dysplasia. The presence or absence of
abnormality on neuroimaging was comparable in both groups
and so were the different abnormalities on neuroimaging.

3.2.5. EEG ndings

EEG was done in 33 (75%) patients, and in 24 of the 28 who
responded well to treatment and nine of the 16 who did not.
Among the non-responders, EEG could be done in only nine of 16
patients due to technical reasons. All these 16 patients had unmistakable clinical evidence of ongoing seizure activity. EEG ndings
in treatment responders have been summarized subsequently.

The secondary outcome measures in this study were recurrence

of seizures within 24 hours after control of SE, drug related adverse
effects, neurological outcome at discharge as assessed by the functional independence measure (FIM; good outcome if FIM score of
57, poor if 14), need for ventilatory assistance, and mortality
during hospitalization. In the study group, 15 patients (34.1%)
had a recurrence of seizures within 24 hours, seven (15.9%)
showed poor neurological outcome at discharge as determined
by FIM, 10 (22.7%) required ventilatory assistance, and four
(9.1%) patients died during the hospitalization. None of the
patients treated with LEV (group B) had adverse effects while
two of the PHT treated patients (group A) developed hypotension.
3.4. Comparison of various primary and secondary outcome measures
between the two groups

3.3. Results of primary and secondary outcome measures in the study

group (n = 44)

The results of the following comparisons are summarized in

Table 2.

The primary outcome measure in this study was control of SE

within 30 min of start of infusion of the study drug. Seizures were
controlled with either study drug in 28 (63.63%) patients, while 16
(36.37%) required additional treatment. Scalp EEG was carried out
in 24 of 28 patients (12 from each group) after a mean of
3.24 hours (range: 18). The remaining four patients in whom
EEG was not done had recovered completely within 1 hour and
therefore EEG was not carried out (all four patients had past history of seizures). EEG was normal in 15 patients and showed theta
activity in nine. One patient out of these nine had occasional
generalized epileptiform discharges and two had evidence of focal
spikes not amounting to electrical SE.

3.4.1. Primary outcome measure

PHT achieved control of SE in 15 (68.2%) patients and LEV in 13
(59.1%) patients. There was no statistically signicant difference
between the two groups with respect to the primary outcome
measure.
3.4.2. Secondary outcome measures
Seizure recurrence within 24 hours was seen in nine (40.9%)
patients in the LEV group compared to six (27.3%) in the PHT
group. Two patients in the PHT group had adverse drug reactions
while none in the LEV group had any drug related side effects.
The nal neurological outcome at discharge was good (as dened

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S. Chakravarthi et al. / Journal of Clinical Neuroscience 22 (2015) 959963

Table 2
Comparison of primary and secondary outcome measures between SE patients treated with PHT or LEV
Parameter
Control of SE within 30 minutes
Recurrence of seizures within 24 hours
Final outcome at discharge

Need of ventilatory assistance

Death
Adverse drug reaction

Y
N
Y
N
Good
Poor
Y
N
Y
N
Y
N

Group A PHT (n = 22)

Group B LEV (n = 22)

p value

15
7
16
6
18
4
6
16
2
20
2
20

13
9
13
9
19
3
4
18
2
20
0
22

0.53
0.34
0.68
0.47
1
0.88

LEV = levetiracetam, N = no, PHT = phenytoin, SE = status epilepticus, Y = yes.

Final outcome based on functional independence measure: good = 57, poor 14.

by FIM scores of 57) in 19 (86.4%) patients in the LEV group as

opposed to 18 (81.8%) in the PHT group. Four (18.2%) patients in
the LEV group and six (27.3%) in the PHT group required ventilatory assistance. Four (9.1%) patients died, two from each group.
There was no statistically signicant difference between the two
groups with respect to all secondary outcome measures.

4. Discussion
SE is an acute neurological emergency with substantial mortality and morbidity if not treated promptly. The traditional drugs for
management of SE include PHT, fosphenytoin, phenobarbitone and
benzodiazepines. All these drugs have serious side effects including respiratory compromise and hypotension. Moreover, these
drugs fail to control status in at least 33% of patients. Therefore,
there is need for more potent and less toxic drugs. LEV, a relatively
new antiepileptic drug, can be a viable and practical option in the
second-line management of SE given its minimal known side effect
prole, limited drug interactions and availability in IV formulation
[20]. Though LEV is being increasingly used for management of SE,
there is paucity of data supporting its role in SE and comparisons of
its efcacy with other second-line drugs.
The mean age and sex distribution of our patient population
was similar to that described previously [2123] although patients
with a past history of epilepsy (n = 31, 70.4%), was higher than in
previous reports [1]. Among these 31, only 14 (45.2%) had good
compliance to their medications.
The approximate total seizure duration prior to admission was
63.98 SD 78.32 min which was lower when compared to previous studies [24]. The reason for shorter delay may be due to easy
access to emergency services and also because most of the patients
were from adjoining areas.
Among the causes of SE, neuroinfections were the most common (40.9%), followed by prior gliosis related to old head trauma
or neurosurgery (15.9%) and infarcts (9.1%) [25]. Neuroinfections
accounted for only 9% of total causes of SE in western studies as
opposed to a signicantly higher proportion in developing
countries.

4.1. Primary outcome measure

In a previous study [26], LEV controlled SE in 76.3% of patients
as opposed to 59.1% in our study. The main reason for the discrepancy may be LEV being used as 1st line agent in that study as
opposed to a 2nd line agent (failure of lorazepam to control SE) in
the present study. There was no statistically signicant difference

between the two drugs implying LEV was as effective as PHT in

controlling SE.

4.2. Secondary outcome measures

Recurrence of seizures within 24 hours was seen in 34.3% of
patients and a good neurological outcome in 84.1%. These observations were comparable to previously described studies [26,27].
Adverse effects with PHT were noticed in 9.1% of patients akin to
former reports [28]. The difference in ethnic background of
patients might have resulted in the varied frequency of adverse
effects observed with LEV in our study when compared to that
by Misra et al. [29] A lesser requirement for ventilator assistance
(22.7%) in contrast to 31.8% in the study by Misra et al. [26] may
be due to shorter duration of SE at presentation.
There was no signicant difference between the LEV and PHT
groups with respect to all the secondary outcome measures.
Thus, LEV was as effective as PHT with regard to secondary outcome measures as well as primary. We found no available data
in the literature to compare this observation.

4.3. Limitations
Our study has several limitations. First, the smaller sample size.
Second, there remained a possibility of bias as double blinding
could not be carried out mainly due to ethical reasons. Third,
EEG could not be carried out in all the patients as few had a rapid
recovery. Finally, patients whose SE was controlled with
Lorazepam were excluded from the study.

5. Conclusion
LEV is as effective as PHT with respect to all the outcome measures. Favoured by its relative ease of administration and lack of
continuous monitoring, LEV can be an attractive alternative to
PHT in management of SE. This randomized open label study
provides rst hand evidence for efcacy and safety of LEV compared with PHT in SE patients.

Conicts of Interest/Disclosures
The authors declare that they have no nancial or other conicts of interest in relation to this research and its publication.

S. Chakravarthi et al. / Journal of Clinical Neuroscience 22 (2015) 959963

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