The present prospective randomized comparative study was conducted in the Department of Pharmacology in collaboration with Department of Medicine at Teerthanker Mahaveer Medical College & Research Centre (TMMC&RC), Moradabad, Uttar Pradesh, during the period from April 2014 to March 2015, on adult patients suffering from idiopathic generalized tonic-clonic seizure (GTCS). Patients were included in the study group on the basis of inclusion and exclusion criteria. This study was approved by Institutional Ethics Committee. A written informed consent was obtained from each patient of the study group.

(a) Age 18 years or above, (b) Newly diagnosed idiopathic generalized tonic-clonic seizures, (c) Patient had experienced clearly observable minimum of two or more generalized tonic-clonic seizures in the preceding one year, (d) Normal general and neurological findings on clinical examination, (e) Normal features in computed tomography (CT Scan) / magnetic resonance imaging (MRI) of brain, (f) Normal intelligence.

(a) Secondary generalized tonic–clonic seizures; (b) Progressive neurological disorder; (c) A psychiatric disorder requiring medication; (d) Clinically significant chronic hepatic, renal and cardiac conditions; (e) Any disease that could interfere with drug absorption, distribution, metabolism, or excretion; (f) Long term co-medication with other drugs; (g) Suspected poor compliance; (h) Pregnant or lactating women; (i) Had been treated with investigational antiepileptic drugs in previous one year.

A detailed history was obtained from patients, relatives or witnesses about the pattern of seizures in Out Patient Department/Indoor Patient Department of Medicine, TMMC&RC. Seizure type was based on the clinical information available.

All the patients underwent general, neurological and other systemic examinations. Investigations included complete blood count, plasma glucose, serum alanine aminotransferase, serum aspartate aminotransferase, serum gamma–glutamyltransferase, blood urea, serum creatinine, CT / MRI imaging of brain, tests for HIV I & II, urinalysis, EEG. All 60 patients were divided into two equal number groups in a random fashion with the help of table of random numbers. Randomization was coordinated separately within the two centers in TMMC&RC, and the identity of allocated treatment was not masked. VPA group patients (n=30) received 200 mg/300mg/500mg enteric-coated non-sustained release sodium valproate tablet. LTG group patients (n=30) received lamotrigine 25mg / 50mg /100mg dispersible non-sustained release tablet.

Valproic acid was initiated at 10 mg/kg/day in two to three divided doses. Dose was increased by 5 mg/kg/day every 3 days until seizures were controlled, intolerable side effects occurred, or a maximum dose of 30 mg/kg/day had been reached. Lamotrigine was initiated at 0.5 mg/kg/day in two divided doses for 2 weeks, followed by 1.0 mg/kg/day for additional two weeks. Thereafter, dose was increased by 1 mg/kg/day until seizures were controlled, intolerable adverse effects occurred, or a maximum dose of 12 mg/kg/day had been reached.

Each patient was advised to visit in the medicine outpatient department of TMMC & RC at monthly interval for 12 months follow-up. At each visit, the evaluation included questioning of the patients or relatives (external observers) about presence or absence of clinical features of generalized tonic-clonic seizures and adverse drug reactions. Medical examination was also done and baseline laboratory investigations (haematological and biochemical) were repeated at the visit. Contact with patients was also maintained through telephone/mobile calls.

Effectiveness was assessed by reduction from baseline in the percentage of patients remaining seizure-free and by reduction from baseline in the mean number of seizures per month, after 12 months follow-up. For this purpose all patients were provided with diaries to record regularly the number and time of occurrence of seizure. If the patient remained seizure-free, ‘none’ was recorded in the diary every day. Patients were also instructed to record adverse event in the seizure diary.

The control of seizure was classified as followed:

(a) Excellent control: seizure–free.

(b) Good control: >/ = 50% reduction in seizure frequency from baseline.

(c) Poor control: <50% reduction in seizure frequency from baseline.

Adverse effects were analyzed by Naranjo Adverse Drug Reaction Probabilty Scale and causality assessment was done in every adverse effect reported. Each adverse drug reaction was assigned to a probability category from the total score as follows: definite if the overall score was 9 or greater, probable for a score of 5 to 8, possible for 1 to 4 and doubtful if the score was 0 [8].

Data was obtained in mean, standard deviation and number (n) and percentage (%) and was analysed by unpaired student t-test. The significance was determined by using Chi-square test. All data were analysed with statistical software SPSS version 21.0.

All 60 patients enrolled for the study had newly diagnosed idiopathic generalized tonic-clonic seizures. Age, sex and duration of epilepsy were comparable in both valproic acid and lamotrigine study groups.

The study group included 37 males and 23 females, ranging in age from 18 to 70 years [Table/Fig-1,2].

After three months of treatment, 16 (53.33%) patients taking valproic acid and 8 (26.67%) patients taking lamotrigine group were seizure-free. At six months, seizure freedom was observed in 19 (63.33%) patients taking valproic acid and 14 (46.67%) patients taking lamotrigine. At the last observation after 12 months followup, 23 (76.67%) patients taking valproic acid and 17 (56.67%) patients taking lamotrigine were seizure-free. This difference was statistically significant (p < 0.03) [Table/Fig-3,4].

In valproic acid group, mean seizure frequency at baseline was 5.17 per month and after 12 months of treatment it decreased to 1.70 per month. In lamotrigine group patients, mean seizure frequency at baseline was 4.93 per month and after 12 months of treatment it decreased to 2.43 per month. Statistical analysis revealed significant difference (p < 0.001) [Table/Fig-5].

Adverse effects were recorded in 9 (30.00%) patients of valproic acid group and 17 (56.66%) in lamotrigine group patients. Sedation, ataxia and tremor were recorded in patients taking valproic acid but these symptoms responded to a decrease in dosage. Skin rash developed within three months in 3 (10.00%) patients taking lamotrigine, they withdrew from the study [Table/Fig-6]. Flow chart of the study participants is presented in [Table/Fig-7].

[Table/Fig-7]:

Flow chart of the study participants.

The present prospective randomized comparative study evaluated the effectiveness of valproic acid and lamotrigine as first-line drug in the treatment of newly diagnosed idiopathic generalized tonic-clonic seizures in adults. The valproic acid was noticed to have better effectiveness profile than lamotrigine. A total of 76.67% patients treated with valproic acid and 56.67% patients treated with lamotrigine became seizure free after 12 months follow-up.

The present study findings are consistent with studies conducted by Steinhoff et al., Marson et al., Nicolson et al., and Mazukiewicz-Beldzinska et al., who have also reported valproic acid superiority over lamotrigine as first-line monotherapy in newly diagnosed idiopathic generalized tonic-clonic seizures in adults and is inconsistent with Stephen et al., study which has reported valproic acid as well as lamotrigine monotherapy to have equal efficacy in the same group of patients [9–13]. Many non-comparative studies have also reported effectiveness of valproic acid as well as lamotrigine monotherapy in newly diagnosed idiopathic generalized tonic-clonic seizures in adults [14–18].

The seizure- free rate observed in the present study (76.67%) in valproic acid group was higher than Nicolson et al., (52.10%), Stephen et al., (47%), Coppola et al., (70%), Trinka et al., (64.50%) and lower than Steinhoff et al., (83.30%) [9,11,13,14,17]. The seizure free rate in lamotrigine group in the present study (56.67%) was higher than Nicolson et al., (16.70%), Stephen et al., (47%) and lower than Steinhoff et al., (60.60 %), Coppola et al., (60%), Steinbaugh et al., (66.50%), Yamamoto et al., (80%), Rosenow et al., (64.50%) [9,11,13–16,18].

In the present study, adverse effects were recorded in 30% cases in valproic acid group and 56.66% cases in lamotrigine group. The commonest adverse effects noticed were gastrointestinal symptoms, headache and skin rash in lamotrigine group and gastrointestinal symptoms, sedation, ataxia and tremor in valproic acid group. In valproic acid group, they were tolerable and did not require withdrawal of drugs but three patients of lamotrigine group withdrew because of dermatological adverse effects.

The incidence and pattern of adverse effects observed in the present study were consistent with previous studies except Yamamoto et al., study which reported higher (82% cases) adverse effects in lamotrigine group [16]. Withdrawal of lamotrigine due to dermatological responses has also been reported by Marson et al., and Mazurkiewicz-Beldzinska et al., [9,12].

The results of the present study are significant, in the context using the drugs on Indian patients. Confounding variable in the present study was social class.

The limitations of present study were that serum levels of valproic acid and lamotrigine were not measured due to lack of facilities, patients number were limited and follow-up was done for one year only.

Both valproic acid and lamotrigine are effective as first-line monotherapy for the treatment of newly diagnosed adults with idiopathic generalized tonic-clonic seizures but valproic acid is preferable to lamotrigine because of being more effective and safe. Long term studies with large population are needed for further evaluation of these drugs.