Seizure: European Journal of Epilepsy
Volume 19, Issue 3 , Pages 195-197, April 2010

Long-term efficacy of valproate versus lamotrigine in treatment of idiopathic generalized epilepsies in children and adolescents

Department of Developmental Neurology, Chair of Neurology, Medical University of Gdańsk, Poland

Received 11 October 2009; received in revised form 19 January 2010; accepted 22 January 2010. published online 18 February 2010.

Article Outline

Abstract 

Purpose

In order to estimate and compare the long-term effectiveness of lamotrigine (LTG) versus valproate (VPA) monotherapy in treatment of newly diagnosed idiopathic generalized epilepsies (IGE) the following study was performed.

Methods

Medical records of 214 children and adolescents suffering from IGE were analyzed. 132 of them were on VPA monotherapy, 82 on LTG. The majority of patients had juvenile myoclonic epilepsy – 98, the rest: juvenile absence epilepsy – 32, childhood absence epilepsy – 53 and epilepsy with a tonic–clonic seizures on awakening – 12, others – 19. Mean age of the patients was 8.9 years (range 4–16 years). The mean time of treatment was 28 months, time of observation 40 months. In order to estimate retention rates and factors predicting successful treatment with LTG and VPA we used Kapplan–Meyer analysis and Gehan tests.

Results

Data analysis showed significantly longer retention rates with VPA versus LTG treatment in overall rates as well in all syndromes subgroups. After 12 months of therapy 69% stayed on LTG therapy versus 89% on VPA, after 24 months 57% versus 83% respectively. VPA showed comparable efficacy in all IGE syndromes where LTG showed better efficacy in childhood and juvenile absence epilepsy than in juvenile myoclonic epilepsy. The shorter duration of treatment with LTG was due to lack of efficacy.

Conclusions

Our results show the superiority of VPA versus LTG treatment in idiopathic generalized epilepsy syndromes.

Keywords: Idiopathic generalized epilepsy, Lamotrigine, Valproate

 

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1. Introduction 

Idiopathic generalized epilepsies (IGE) are genetically determined and affect otherwise normal people of both sexes and races. They manifest with generalized tonic–clonic seizures, typical absence seizures and myoclonic jerks alone or in varying combinations and severity. In general IGE respond to treatment, with approximately 80% becoming fully controlled 1. Monotherapy is considered to be the goal in the first line pharmacologic management of epilepsy as it is effective, well tolerated and associated with low costs, better patient compliance and higher quality of life. Although conventional anti-epileptic drug (AED) valproate and the modern AED lamotrigine are identified as optimal first line or second-line monotherapy for idiopathic generalized epilepsies, effectiveness and course of treatment vary between the patients and are still a matter of discussion. Lamotrigine has been proposed as first line new AED in treatment of childhood absence, juvenile absence, juvenile myoclonic and generalized tonic–clonic epilepsy according to NICE guidelines 2. Valproate is a very effective anticonvulsant drug (AED) for IGE however it carries some risks connected with it's side effects profile. There is still limited evidence with head to head comparision of this two agents in clinical settings 3. The goal of present study was to estimate and compare the long-term effectiveness of lamotrigine (LTG) versus valproate (VPA) monotherapy in treatment of idiopathic generalized epilepsies (IGE).

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2. Materials and methods 

Medical records of 214 children and adolescents suffering from IGE (patients of Developmental Neurology Department and Outpatient Clinic during 1999–2008) were analyzed. All of the patients were newly diagnosed with IGE and previously not treated. 132 of them were on VPA monotherapy, 82 on LTG. The majority of patients had juvenile myoclonic epilepsy – 98, juvenile absence epilepsy – 32, childhood absence epilepsy – 53 and epilepsy with a tonic–clonic seizures on awakening – 12, others – 19 (included 4 patients presenting absences with eyelid myoclonias, 5 with myoclonic absences and 10 who did not fulfill criteria for “pure” childhood absence epilepsy (photosensitivity, early in the course of disease appearance of tonic–clonic seizures). Mean age of the patients was 8.9 years (range 4–16 years). The group characteristics are presented in Table 1. The mean time of treatment was 28 months, time of observation 40 months. Mean doses of LTG were 8mg/kg/day (range 5–13mg/kg/day), for VPA 25mg/kg/day (range 20–32mg/kg/day). In order to estimate retention rates and factors predicting successful treatment with LTG and VPA we used Kapplan–Meyer analysis and Gehan tests.

Table 1. Group characteristics.
LTGVPA
Number of patients82132
Males/Females27/5562/70
Mean age of seizure onset8.5 (4–16)9.2 (4–16)
Mean weight (kg)32,2 (17.2–101)27.1 (18.5–72.2)

Types of epileptic seizures
Myoclonic3982
Absence4159
Tonic–clonic2532

Types of epilepsy syndrome
Juvenile myoclonic epilepsy (JME)3563
Childhood absence epilepsy (CAE)2132
Juvenile absence epilepsy (JAE)1517
Epilepsy with tonic–clonic seizures on awakening75

Others415

Note: Some patients had more than one type of epileptic seizure.

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3. Results 

Data analysis showed significantly longer retention rates with VPA versus LTG treatment in overall rates as well in major syndromes subgroups. After 12 months of therapy 69% of patients stayed on LTG therapy versus 89% on VPA, after 24 months 57% versus 83% respectively (Fig. 1). VPA showed comparable efficacy in all IGE syndromes, where LTG showed better efficacy in childhood and juvenile absence epilepsy than in juvenile myoclonic epilepsy (Table 2). The shorter duration of treatment with LTG was due to lack of efficacy (Table 3). There were no differences in mental status as well as severity of EEG changes in subgroups of patients who continued or discontinued the treatment. Side effects were important reasons for discontinuation of the therapy. 10 patients receiving VPA ceased the treatment because of: weight gain, hair loss, diarrhoea, stomach pain. 2 patients treated with LTG discontinued further treatment due to rash.

Table 2. Mean duration (months) of treatment for all patients with IGE and according to major types of epilepsy syndromes (JME – juvenile myoclonic epilepsy or CAE – childhood absence epilepsy).
All patientsJMECAE
Number of patientsMeanRangeNumber of patientsMeanRangeNumber of patientsMeanRange
VPA13234.61–696338.11–693239.81–69
LTG8219.21–57358.41–422126.11–57
Table 3. Reason of discontinuation of lamotrigine and valproate in patients with idiopathic generalized epilepsy and mean duration (months) of treatment in patients who discontinued the drug.
Discontinued (number of patients) (%)Mean duration of treatmentLack of efficacyAdverse effectsOthersLost to follow up
Valproate28/19.712.3141022
Lamotrigine47/57.39.739233

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4. Discussion 

Our study is one of the few comparing the retention rates of new AED–LTG with classical AED–VPA, that has well established efficacy in this type of epilepsy. This is an observational study performed in a single centre, thus there was no risk of methodological differences which could be present in studies where patients from several referral centers are included. It seems to be important, that all the patients were not previously treated with any AED.

The sample group is relatively large and we hope that the results reflect the reality in clinical practice. The VPA and LTG groups, as well as the subgroups of different epileptic syndromes (JME, CAE, JAE) were similar according to age. There were significantly more females in LTG group. LTG was prescribed especially to girls because of potential lack of adverse events crucial for female-teenagers such as hyperandrogenism and potential teratogenity 4, 5, 6, 7, 8 as well for patients who were overweight or had a tendency to gain on weight.

Long-term tolerability of AEDs in children is important, because the adverse event profile of the drug is often a major determinant in the choice of therapy.

However, in our study better tolerability and relatively small rate of side effects did not correlate with longer period of therapy. Principal reason of earlier discontinuation of therapy in LTG group was referred to lower efficacy in comparison to VPA group.

We find it noteworthy that valproate provides good long-term maintenance of seizure control. At the same time, we did not find the support to previous statements that lamotrigine could serve as alternative treatment to valproate in forms of IGE 9, 10, 11, 12, 13, 14.

Comparability is never perfect in a non-randomized study, but it is unlikely that the differences in outcomes could be a result of using inappropriate doses of some AED. The doses of the AED surveyed in the study were within the recommended target levels 15. This study was not a controlled trial and in these patients drugs were normally adjusted depending on the efficacy and the tolerability.

The duration of treatment with AED (retention rate) strongly associates with two major factors – the efficacy and the adverse events. In many cases a profit of successful treatment of epilepsy—which means reduction or even elimination of seizures—overweighs the expense of adverse effects. For this reason, further comparable long-term studies should be performed in order to assess the significance of side effects in particular age groups of patients with marked improvement on valproate therapy.

Discontinuations of AED owing to adverse effects occurred quite early in the course of treatment, usually within the first six months. In our study adverse effects were the reason of discontinuation in 5.6% of patients (7.6% on VPA and 2.4% on LTG). It shows, that LTG was better tolerated but the lack of efficacy was crucial for the smaller retention rate with this drug. 47.6% of patients on LTG discontinued the study due to lack of efficacy versus 10.6% on VPA therapy.

Data in the literature suggests that the primary reason for fail the newly introduced anti-epileptic treatment is a lack of efficacy rather than adverse effects. Proper decision of neurologist is essential as inadequate response to initial treatment is believed to be a poor prognostic factor in further course of epilepsy 16.

Especially for children and adolescents it is extremely important to start the therapy with the drug, that provides the patient a greater chance for being seizure free (between others, also from the social and psychological point of view). It is important to mention that in long-term therapy with VPA it is possible to maintain the therapeutic effect on reduced dose with the benefit of reduced adverse effects including teratogenicity 17.

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5. Conclusions 

In conclusion, our study suggests that there are clinically significant differences between lamortrigine and valproate in terms of efficacy in idiopathic generalized epilepsies. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.

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References 

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PII: S1059-1311(10)00015-4

doi:10.1016/j.seizure.2010.01.014

Seizure: European Journal of Epilepsy
Volume 19, Issue 3 , Pages 195-197, April 2010

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