Brief CommunicationBehavioral effects and somnolence due to levetiracetam versus oxcarbazepine — a retrospective comparison study of North Indian patients with refractory epilepsy
Introduction
Behavioral abnormalities and somnolence are common problems affecting quality of life among patients with drug-refractory epilepsy. Levetiracetam (LEV) is an antiepileptic drug (AED) with multiple mechanisms of action, and its effectiveness in seizure control is based on randomized controlled trials (RCTs) for its use both as add-on therapy as well as monotherapy for various focal and generalized epilepsy syndromes. Its use has increased tremendously over the last decade, because of the multiple modes of action and the broad spectrum of its coverage [1], [2], [3], [4].
There are already some meta-analyses available on the safety of LEV in specific syndromes and at least one that combines data from all RCTs for various epilepsy syndromes [5], [6]. However, most of the RCTs were conducted to test the efficacy of this drug, and while tolerability details were collected and reported, many adverse effects which have an overlap with chronic epilepsy itself, as far as causation is concerned, most remarkably, the behavioral effects, were possibly underreported.
Oxcarbazepine (OXC) is another AED, which has been recommended, found efficacious, and used extensively over the last two decades, especially in the pediatric population [7], [8], [9]. A number of studies have also reported safety and the adverse effect profile of the drug [10], [11], [12]. Excessive somnolence is a frequent side effect of many AEDs and, in our observation, very common with OXC. However, there are not many studies addressing this important effect of the drug, which can limit its use or reduce AED retention rates.
Since valproate (VPA) is one AED extensively studied for its adverse effects in various populations and remains a commonly used broad-spectrum AED with high efficacy [7], the comparison of adverse effects of LEV and OXC with those of VPA would be appropriate, given a similar patient population with similar frequency of AED prescription for the three AEDs.
Most of the studies reporting adverse effects suffer from heterogeneity in populations studied, endpoints used to discontinue or reduce dosage of medication, and more so, terms used for categorizing adverse effects [5], [6], [10].
Moreover, given the possibility of differences across ethnic and geographically diverse populations, it would be worthwhile to study the adverse effect profile of these AEDs in an Indian population.
This study was, therefore, conducted to evaluate behavioral abnormalities and somnolence among patients with drug-refractory epilepsy (DRE) being treated with LEV and/or OXC compared with those receiving VPA in a naturalistic setting.
Section snippets
Methods
This was a retrospective chart review-based study of consecutive patients attending our intractable epilepsy clinic over a 2 1/2-year period, between June 2013 and November 2015.
Charts of patients aged 6–60 years, with either or both focal or generalized epilepsy types, with seizure frequency of at least one seizure a month, who had been initiated on either or a combination of LEV, VPA, or OXC, were included for analysis. Only those among these for whom follow-up information was available for at
Results
Among a total of 445 patients screened, 292 (93 F, median age: 21 years [range: 8–54]) fulfilled inclusion criteria. Epilepsy was classified as focal in 237 and generalized in 55 patients. Median epilepsy duration was 11 years (range: 2–36 years). Median seizure frequency was 2–4 seizures per month, while 67 patients had daily seizures (Table 1).
Levetiracetam had been introduced in 114 patients, VPA in 134, and OXC in 151 during the study period. Twenty-three were on LEV + OXC, 27 on LEV + VPA, and 33
Discussion
This study is important for highlighting the commonness of behavioral disturbances as well as somnolence among patients with refractory epilepsy, in whom LEV or OXC or VPA was started in a real-world clinical setting. We observed that up to 20% patients in whom LEV is initiated may report behavioral disturbances of varying severity and type, leading to discontinuation of the drug in up to 9%; while nearly 10% patients report excessive somnolence on OXC initiation.
There are few studies on the
Conclusion
This observational highlights important differences in the adverse effect profile of levetiracetam and oxcarbazepine, commonly used for the treatment of refractory epilepsy. Behavioral effects are common with levetiracetam and somnolence with oxcarbazepine, when initiated in this population.
Conflict of interest
None of the authors have any conflict of interest to declare.
References (16)
- et al.
Efficacy and tolerability of levetiracetam during 1-year follow-up in patients with refractory epilepsy
Seizure
(2003) - et al.
A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy
Seizure
(2000) - et al.
The adverse event profile of levetiracetam: a meta-analysis on children and adults
Seizure
(2015) - et al.
Behavioral side-effects of levetiracetam in children with epilepsy: a systematic review
Seizure
(2014) - et al.
The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial
Lancet
(2007) - et al.
Prognostic factors for time to treatment failure and time to 12 months of remission for patients with focal epilepsy: post-hoc, subgroup analyses of data from the SANAD trial
Lancet Neurol
(2012) - et al.
Oxcarbazepine for treatment of partial epilepsy: a review and recommendations for clinical use
Epilepsy Behav
(2000) - et al.
Central nervous system adverse effects of new antiepileptic drugs — a meta-analysis of placebo-controlled studies
Seizure
(2008)
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