Journal of Clinical Neuroscience 22 (2015) 959–963
`
`Contents lists available at ScienceDirect
`
`Journal of Clinical Neuroscience
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j o c n
`
`Clinical Study
`Levetiracetam versus phenytoin in management of status epilepticus
`⇑
`, Ashish Bhalla, Parampreet Singh
`
`Sudheer Chakravarthi, Manoj Kumar Goyal, Manish Modi
`
`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
`
`a b s t r a c t
`
`Article history:
`Received 2 August 2014
`Accepted 14 December 2014
`
`Keywords:
`Levetiracetam
`Phenytoin
`Randomized trial
`Seizures
`Status epilepticus
`
`The purpose of this study was to compare safety and efficacy 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 efficacy 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.
`Ó 2015 Elsevier Ltd. All rights reserved.
`
`1. Introduction
`
`Status epilepticus (SE) is a common neurological emergency
`with mortality rates ranging from 3–39% 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 135–155 per 100,000 in patients less than
`1 year of age and 63–86 per 100,000 in patients older than 60 years
`[1]. About 10–25% 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 first-line medications of SE which includes intravenous
`(IV) benzodiapines [5,6]. Since first-line therapy fails to control at
`least 35–45% 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/Ó 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 efficacy in SE [10].
`LEV was first introduced in 1999 and its use has rapidly spread
`due to its pharmacological properties (minimal protein-binding
`and drug–drug interactions) and a favourable side effect profile
`[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 efficacious in management of sei-
`zures and is also being increasingly used in management of SE
`[14–16]. 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
`
`ARGENTUM Exhibit 1151
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
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`Page 00001
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`S. Chakravarthi et al. / Journal of Clinical Neuroscience 22 (2015) 959–963
`
`determine the role of LEV as an alternative to PHT and compare
`efficacy and safety in treatment of SE.
`
`3. Results
`
`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 hos-
`pital 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 first 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 defined 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 fulfilled the
`definition 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 elec-
`troencephalography (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, neurologi-
`cal outcome at discharge as assessed by functional independence
`measure (FIM; good outcome if FIM score of 5–7, poor if 1–4), 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 Fisher’s exact
`test for categorical variables and the Mann–Whitney 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).
`
`3.1. Patient demographics
`
`This prospective study comprised 44 patients with SE. Forty-
`one 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: 14–75). 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: 20.0–60.0) 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: 16.25–60]) while among the non-responders
`it was 113.13 ± SD 109.6 min (median IQR of 60 min [30–165]).
`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 symp-
`tomatic (neurocysticercosis, tuberculomas, viral encephalitis, cere-
`bral 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 leu-
`cocyte counts, platelet counts, blood glucose, renal and liver func-
`tion tests,
`serum electrolytes,
`calcium, phosphorus
`and
`magnesium, cerebrospinal fluid 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 findings
`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
`
`Page 00002
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`
`Table 1
`Comparison of various parameters between SE patients treated with PHT or LEV
`
`S. Chakravarthi et al. / Journal of Clinical Neuroscience 22 (2015) 959–963
`
`961
`
`Parameter
`
`Age* (years)
`Duration of SE* (min)
`Type of SE, n
`
`Sex, n
`
`Positive past history of seizures
`
`Etiology of SE
`Idiopathic
`Acute symptomatic
`Remote symptomatic
`
`Laboratory parameters
`Hypocalcemia
`Leucocytosis
`
`STESS
`0
`1
`2
`3
`4
`Neuroimaging abnormality
`
`Type of abnormality on neuroimaging
`Normal
`Calcified granuloma
`Neurocysticercosis
`Chronic infarct
`Gliotic scar
`Viral encephalitis
`Cerebral venous sinus thrombosis
`Hypoparathyroidism
`Tuberculoma
`Focal cortical dysplasia
`
`Group A PHT (n = 22)
`
`Group B LEV (n = 22)
`
`31.82 ± 12.68
`72.05 ± 48.57
`GCSE, 21
`Focal, 1
`M, 15
`F, 7
`14
`
`39.00 ± 18.40
`55.91 ± 73.75
`GCSE, 20
`Focal, 2
`M, 12
`F, 10
`17
`
`7
`3
`12
`
`5
`7
`
`2
`9
`4
`7
`0
`15
`
`8
`0
`7
`1
`2
`1
`1
`1
`1
`0
`
`6
`10
`6
`
`1
`7
`
`2
`10
`5
`3
`2
`16
`
`6
`1
`4
`3
`5
`1
`0
`0
`1
`1
`
`p value
`
`0.140
`0.501
`1.0
`
`0.128
`
`0.322
`
`0.53
`
`0.18
`1
`
`0.51
`
`0.74
`
`0.68
`
`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, hypoparathy-
`roidism 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 findings
`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 unmis-
`takable clinical evidence of ongoing seizure activity. EEG findings
`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 func-
`tional independence measure (FIM; good outcome if FIM score of
`5–7, poor if 1–4), 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: 1–8). 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 his-
`tory 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 significant 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 final neurological outcome at discharge was good (as defined
`
`Page 00003
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`S. Chakravarthi et al. / Journal of Clinical Neuroscience 22 (2015) 959–963
`
`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
`
`Group A PHT (n = 22)
`
`Group B LEV (n = 22)
`
`p value
`
`Y
`N
`Y
`N
`Good
`Poor
`Y
`N
`Y
`N
`Y
`N
`
`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 = 5–7, poor 1–4.
`
`by FIM scores of 5–7) 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 ventila-
`tory assistance. Four (9.1%) patients died, two from each group.
`There was no statistically significant difference between the two
`groups with respect to all secondary outcome measures.
`
`4. Discussion
`
`SE is an acute neurological emergency with substantial mortal-
`ity 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 includ-
`ing 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
`profile, 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 efficacy with other second-line drugs.
`The mean age and sex distribution of our patient population
`was similar to that described previously [21–23] 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 pre-
`vious 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 com-
`mon (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 significantly higher proportion in developing
`countries.
`
`4.1. Primary outcome measure
`
`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 observa-
`tions 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 significant 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 out-
`come 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 mea-
`sures. 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 first hand evidence for efficacy and safety of LEV com-
`pared with PHT in SE patients.
`
`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 discrep-
`ancy 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 significant difference
`
`Conflicts of Interest/Disclosures
`
`The authors declare that they have no financial or other con-
`flicts of interest in relation to this research and its publication.
`
`Page 00004
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`

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