Behavioral effects and somnolence due to levetiracetam versus oxcarbazepine — a retrospective comparison study of North Indian patients with refractory epilepsy

Highlights

• Behavioral effects and sleepiness with levetiracetam and oxcarbazepine versus valproate in 445 patients with epilepsy

• Behavioral disturbances in 20% of patients with levetiracetam

• Daytime somnolence in 10% of patients with oxcarbazepine

Abstract

Purpose

Levetiracetam (LEV) is often chosen early in the treatment of refractory epilepsy; however, its adverse effects have largely been studied as part of clinical trials. Oxcarbazepine and valproate (VPA) are the other commonly used AEDs and, hence, serve as good comparators. This study was conducted to evaluate behavioral abnormalities and somnolence among patients with epilepsy being treated with LEV and/or OXC compared with those receiving VPA.

Method

Data of consecutive patients attending our intractable epilepsy clinic over a 2 1/2-year period were reviewed, and patients with at least one seizure a month, who had been initiated on either or a combination of LEV, VPA, or OXC, were included for analysis. Data regarding behavioral adverse effects, daytime somnolence (EDS), and weight changes were collected apart from those regarding any major effect necessitating dose reduction or discontinuation of the AED.

Results

Among a total of 445 patients screened, 292 (93 F, median age: 21 years [range: 8–54]; 237 focal and 55 generalized epilepsy) fulfilled inclusion criteria. Median epilepsy duration was 11 years. 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 on VPA + OXC. Behavioral disturbances (irritability, obsessive manifestations, aggressiveness, and frank psychosis) were observed in 43 patients; 23 on introduction of LEV (20.2%); LEV was discontinued in 10 (9%). Daytime somnolence was reported by 28 patients, 15 on OXC (10%); 8 received oral modafinil for the same, while none discontinued this AED. Only one patient on LEV and 3 on VPA reported EDS. Menstrual disturbances were reported by 9, weight gain by 3, and severe hair loss by 2 females on VPA.

Conclusion

Behavioral disturbances with levetiracetam are common among patients with refractory epilepsy while somnolence is common with oxcarbazepine. Antiepileptic drugs should be selected with this in perspective.

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.