Clinical Study
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.
960
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
961
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
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
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.
962
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
Y
N
Y
N
Good
Poor
Y
N
Y
N
Y
N
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
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.
4.3. 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.
References
[1] Treiman DM. Status epilepticus. In: Wyllie E, editor. The treatment of epilepsy:
principles and practice. Philadelphia, USA: Lippincott Williams and Wilkins
publishers; 2001.
[2] Chin RF, Neville BG, Peckham C, et al. Incidence, cause, and short-term
outcome of convulsive status epilepticus in childhood: prospective
population-based study. Lancet 2006;368:2229.
[3] Aicardi J, Chervie JJ. Convulsive status epilepticus in infants and children. A
study of 239 cases. Epilepsia 1970;11:18797.
[4] Hauser WA. Status epilepticus: epidemiological considerations. Neurology
1990;40:913.
[5] Eue S, Grumbt M, Mller M, et al. Two years of experience in the treatment of
status epilepticus with intravenous levetiracetam. Epilepsy Behav 2009;15:
4679.
[6] Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med
1998;338:9706.
[7] Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for
generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus
Cooperative Study Group. N Engl J Med 1998;339:7928.
[8] Leppik IE, Derivan AT, Homan RW, et al. Double-blind study of lorazepam and
diazepam in status epilepticus. JAMA 1983;249:14524.
[9] OBrien TJ, Cascino GD, So EL, et al. Incidence and clinical consequence of the
purple glove syndrome in patients receiving intravenous phenytoin. Neurology
1998;51:10349.
[10] Alvarez V, Januel JM, Burnand B, et al. Second-line status epilepticus
treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia
2011;52:12926.
[11] Crepeau AZ, Treiman DM. Levetiracetam: a comprehensive review. Expert Rev
Neurother 2010;10:15971.
[12] Holtkamp M, Othman J, Buchheim K, et al. Predictors and prognosis of
refractory status epilepticus treated in a neurological intensive care unit. J
Neurol Neurosurg Psychiatry 2005;76:5349.
[13] Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the
binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA
2004;101:98616.
963