Epilepsy is a chronic disorder characterized by 2 or 3 recurrent seizures of cerebral origin. It is the second most common neurological condition after headache. The estimated average prevalence of epilepsy is 6.8 per 1000 people in US, 5.5 per 1000 people in Europe, and 1.5 to 14 per 1000 people in Asia, respectively. Epilepsy is classified based on the source of seizure into partial and generalized seizures [
The mainstay of treatment of epilepsy is pharmacological therapy with antiepileptic drugs (AEDs). In epilepsy, optimal treatment is important as the condition is associated with increased morbidity and mortality and unexpected deaths without clear structural or pathological cause [
Till date, there have been a very few studies on the efficacy and safety of LEV and CBZ in partial epilepsy. Hence, this study was undertaken to compare the efficacy and safety of LEV and CBZ as monotherapy in partial epilepsy.
This was a randomized, prospective, open label, comparative monotherapy study. The study was conducted in the Department of Neurology at Vydehi Institute of Medical Sciences and Research Center, Bengaluru, India. The institute is a 1000-bed tertiary care hospital equipped with modern diagnostic and treatment facilities. Patients visiting this hospital come from different geographical regions including Southern Karnataka, Andhra Pradesh, and West Bengal, India, with a fair representation of both urban and rural populations. The patients belong to varied socioeconomic strata. The study was conducted after receiving the approval from the Institutional Ethics Review Board. The duration of the study was one year from January 2013 to December 2013.
The participants were included in the study after obtaining written informed consent. The study inclusion criteria included subjects of age between 18 and 60 years diagnosed newly with focal or partial seizures with or without secondary generalization. The exclusion criteria were pregnant and lactating mothers, patients with nonepileptic seizures, auras or absence of seizures, and patients with acute symptomatic seizures occurring within 14 days of an acute brain injury such as stroke and patients with history of psychiatric illness.
The Neurology OPD was used to recruit participants with newly diagnosed partial epilepsy. The study objectives and process were explained to the patients or their relatives in their own language. Subjects who consented to participate were then interviewed and were divided into two groups by the toss of a coin. Each group recruited 30 participants. Group 1 participants were prescribed Tab LEV, 1000–3000 mg/day/oral; and group 2 participants were prescribed Tab CBZ, 400–1200 mg/day/oral. The participants were started with minimum dose, 500 mg of LEV and 200 mg of CBZ, given twice daily after food and then titrated depending on the seizure control. LEV dose was increased by 500 mg twice daily every 2 weeks up to a maximum of 3000 mg/day if seizure control was not achieved. Similarly, CBZ dose was increased by 200 mg twice daily up to a maximum of 1200 mg/day if seizure control was not achieved. In cases where the seizure was not controlled after titration of drug dose, the participant was shifted to adjuvant therapy based on the clinical condition. The participant was also discontinued from the study.
All the participants were given a diary and were asked to note down any adverse effects (AE). They were advised to come after 4, 12, and 26 weeks after the initiation of therapy for follow-up. During follow-up visits, the participants were thoroughly examined, history of breakthrough seizures was elicited, and any AEs were noted. QOL was assessed by using the QOLIE-10 questionnaire before initiation of the treatment and after 26 weeks of therapy [
The baseline data like demography, efficacy, and AEs were subjected to descriptive statistical analysis and expressed as mean ± SD, frequencies, and percentages. The QOLIE-10 scores were expressed as mean ± SD scores. The categorical variables were compared using Chi-square (
A total of 79 subjects were screened for the study. Out of them, 60 (75.6%) participants who fulfilled the eligibility criteria were randomized into the two study groups. Following is the summarization of the observed results.
Out of 30 participants in CBZ group, 17 were male and 13 were female. Out of 30 participants in LEV group, 13 were male and 17 were female. The mean age of the male participants in CBZ group was
Thirty participants were randomized to both CBZ group and LEV group. In the LEV group, 2 participants dropped from the study, one was lost to follow-up, and one subject had serious AE. Thus, a total of 28 subjects in LEV group were assessed for efficacy. Similarly, 2 subjects in CBZ group were dropped from the study due to AE. Thus, a total of 28 subjects from CBZ group were assessed for efficacy as shown in Figure
Patient disposition in the study.
All participants were followed up at 4, 12, and 26 weeks after the initiation of monotherapy. At the 4th week of follow-up, both groups had equal seizure freedom of 85.72% which is not statistically significant (
Seizure freedom at 4th, 12th, and 26th weeks.
Overall seizure freedom at the end of 6 months.
Participants who experienced at least one AE constituted 36.66% in CBZ group and 40% in the LEV group (
In clinical practice, QOLIE-10 score ranges from 0 to 100. A total score range of less than 50 indicates the poor quality of life, a score from 50 to 70 indicates the optimal QOL, and a score more than 70 implies better QOL. QOL assessment was done in the participants in both groups at 0 weeks and at the end of 24 weeks. The mean QOL score in CBZ group at 0 weeks was
Overall characteristics are shown in Table
Overall characteristics of patients on Levetiracetam and Carbamazepine monotherapy.
CBZ group | LEV group |
|
|
---|---|---|---|
|
|
||
Male mean age | 30.70 ± 2.66 yrs | 22.62 ± 1.152 yrs | 0.0834 |
Female mean age | 29.31 ± 2.44 yrs | 28.18 ± 2.553 yrs | 0.7101 |
Mean BMI | 22.56 ± 0.41 | 21.49 ± 0.41 | 0.0690 |
Pretreatment mean seizure frequency | 2.83 ± 0.19 | 4.2 ± 0.65 | 0.0470 |
Seizure freedom at 4 weeks | 85.72% | 85.72% | 1.0000 |
Seizure freedom at 12 weeks | 89.29% | 93.34% | 0.4595 |
Seizure freedom at 26 weeks | 96.43% | 100% | 0.1212 |
Overall seizure freedom at 6 months | 71.42% | 78.57% | 0.2529 |
QOL at 0 weeks | 31.14 ± 1.83 | 29.76 ± 1.71 | 0.5861 |
QOL at 26th week | 58.41 ± 1.89 | 64.58 ± 2.02 | 0.0302 |
The aim of AED treatment is to achieve seizure freedom with minimal or ideally no AE and with an optimal QOL. Numerous AEDs are licensed as monotherapy for focal seizure in adults. These include the older AED like CBZ. Even though CBZ has many AEs and tolerability issues, it was considered as gold standard first-line drug to treat focal seizures from past many years. In 2013, ILEA has produced an updated review in epilepsy treatment, which highlighted the fact that newer AEDs like LEV and zonisamide have class 1-2 evidence to be used as monotherapy. This is based on regulatory trials showing noninferiority when compared to CBZ for 6-month remission [
The study sample was characterized by its relatively younger age (mean age,
In this study, the efficacy was mainly assessed by seizure freedom rate. According to ILAE, a patient is considered as seizure-free following an intervention after a period without seizures has elapsed equal to three times the longest preintervention interseizure interval over the previous year [
Participants were asked to come for follow-up visits at 4, 12, and 26 weeks after initiation of the drug. The pretreatment mean seizure rate in LEV was
Seizure freedom at 12 weeks of therapy in LEV group was 93.34%, while in CBZ group it was 89.29% (no statistical significance;
In most of the comparative studies of LEV versus CBZ, the main efficacy outcome was seizure freedom rate at 6 months and 12 months. Since this was time bound academic study, we could not follow up the cases for long term.
The final efficacy outcome was assessed on seizure freedom at the end of 6 months. In our study overall seizure freedom rate at the end of 6 months was 71.42% in CBZ group compared to 78.57% in LEV group (
No drug has shown superior efficacy to CBZ in randomized, head to head comparison in newly diagnosed epilepsy patients with partial or generalized tonic-clonic seizures. Though most of the studies clearly mention that newer AEDs are always comparable with older AEDs in efficacy, none of the studies till date showed a superior efficacy with newer AEDs compared to older AEDs. In our study too similar results were obtained; that is, LEV was comparable with CBZ in efficacy but it was not superior to CBZ.
The ultimate goal of treatment of epilepsy is the fact that patients should not have seizures, less AE, and an optimal QOL. In this study, both LEV and CBZ were well tolerated as initial monotherapy. Only 6.66% of patients on CBZ and 3.33% of patients on LEV withdrew from the study due to AE. There was more withdrawal of patients in the CBZ group which correlates to a previous study conducted by Brodie et al. In that study, 19.2% of patients on CBZ versus 14.4% of patients on LEV discontinued due to AE [
In this study, the participants taking CBZ mostly reported AEs like increased sleep (20%) and dizziness (13.33%) similar to the study conducted by Perry et al., where 40% of patients on CBZ reported increased sleep and 10% of patients reported dizziness. There was withdrawal of 2 subjects after 24 hours of initiation of drug, but none of the patients on CBZ reported serious AE.
In this study, subjects assigned to the LEV group most commonly (17.85%) reported behavioral changes in terms of increased aggressive behavior, increased anxiety, and suicidal tendency. Similarly, in Perry et al.’s study, LEV was associated with increased behavioral changes in terms of irritability (30.5%). Many of the case reports do suggest that LEV is associated with increased behavioral changes [
In this study, 2 patients on LEV reported weight gain of 3–5 kg in 3 months. Till date, there have been reports of LEV induced weight loss. Here, weight gain can be correlated with improved QOL. Other AEs observed in this study were giddiness, increased sleep, itching, and nausea.
Long term AEs of CBZ have been reported to be leukopenia, hyponatremia, disturbances of vitamin D metabolism, agranulocytosis, and hepatitis. LEV is a comparatively new drug. The studies till date mention that the drug is well tolerated on long term use. There are reports of discontinuation of the drug due to irritability but this was related to previous history of mood disorders [
The QOL evaluation is a relatively new measure to evaluate patient related outcome of treatment for epilepsy. Recently, other studies have tried to determine the effects of various demographic and clinical variables on the overall QOL among patients with epilepsy [
LEV thus demonstrated better QOL after 6 months of therapy compared to CBZ.
The efficacy of LEV was found to be comparable to CBZ as monotherapy in the treatment of partial seizures. LEV did not show superior efficacy compared to CBZ. Both drugs equally reduced the seizure frequency compared to pretreatment seizure frequency. LEV was equally tolerable to CBZ. LEV and CBZ demonstrated equal incidence of AE. LEV can be safely used as monotherapy in the treatment of partial epilepsy.
The work was conducted when the corresponding author was a postgraduate student at Vydehi Institute of Medical Sciences and Research Centre.
The authors declare that there is no conflict of interests regarding the publication of this paper.