Oxcarbazepine in the treatment of childhood epilepsy

Introduction 

Oxcarbazepine is a keto-derivative of carbamazepine. Despite a similar chemical structure these two compounds have different metabolic profiles. Absorption of oxcarbazepine is rapid and complete. The major metabolite responsible for antiepileptic effect is monohydroxy derivative [1].

In comparative clinical trials, oxcarbazepine was demonstrated to be as efficacious and better tolerated than carbamazepine. Its mechanistic profile is similar to carbamazepine. Oxcarbazepine blocks sustained repetitive firing in cultured spinal cord neurons in a voltage and frequency dependent manner [2]. Additional results from electrophysiologic studies suggest that its active metabolite may mediate some of its antiepileptic effect through an action at high-threshold voltage-gated Ca2+ channels [3].

It is rapidly and completely absorbed after oral intake. In contrast to carbamazepine, oxcarbazepine does not induce hepatic drug metabolism in humans and autoinduction is not an issue. Oxcarbazepine has a lower incidence of allergic reactions and is less neurotoxic [4].

In some of the studies it is reported that 50-100% seizure control can be achieved with oxcarbazepine in 80% of newly diagnosed patients with partial and generalized tonic clonic seizures [5]. It is not effective in absence and myoclonic seizures. The most common side effects are nausea, headache, sedation, dizziness, and asymptomatic hyponatremia [6].

The aim of this study is to evaluate the safety and efficacy of oxcarbazepine as monotherapy in children with partial and generalized epilepsy.

Materials and methods 

This study is an open-label nonrandomized multicenter prospective study. Outpatients with two unprovoked partial or generalized seizures 4 years of age or older were enrolled the study. They were newly diagnosed epilepsy patients and did not use any other antiepileptic drugs previously. Forty-two patients (19 females, 23 males), 5-17 years of age and observed in the Pediatric Neurology Departments of Ege University and 9 Eylül University were included the study. They were diagnosed as partial (n = 17) and generalized (n = 25) epilepsy according to International League Against Epilepsy criteria [7] and had at least two unprovoked seizures.

The mean age was 11.9 ± 3.4 years. The number of patients according to age groups were as follows: 4-6 years (n = 7), 7-9 years (n = 14), 10-12 years (n = 8), 13-15 years (n = 9), and 16-17 years (n = 4). The mean age at seizure onset was 8.9 ± 4 years. Five of the patients had family history of epilepsy.

The seizure types were as follows: complex partial seizure (n = 12), simple partial seizure (n = 4), secondary generalized seizure (n = 1), and generalized tonic clonic seizure (n = 25). Eleven of the patients had symptomatic epilepsy, as follows: cortical dysplasia (n = 1), hippocampal sclerosis (n = 1), kernicterus (n = 1), phenylketonuria (n = 1), multiple sclerosis (n = 1), trauma (n = 1), infection of central nervous system (n = 1), and perinatal asphyxia (n = 4). The epilepsy types and etiology of the patients are provided in Table 1.

Table 1. Etiology and epilepsy types of the patients

	Epilepsy Type	Idiopathic	Symptomatic	Total
	Partial	12	5	17
	Generalized	19	6	25
	total	31	11	42

Blood count, lipid profiles, electrolytes, and liver function tests were studied before treatment and monitored at the first, third, and sixth months.

Electroencephalography, electrocardiography, and magnetic resonance imaging were assessed at the beginning of the therapy. The electroencephalograms were evaluated by the same person for all patients. Magnetic resonance imaging was assessed in the Radiology Department of Ege and Dokuz Eylul University. Oxcarbazepine was begun in the patients with normal cardiologic examination and electrocardiography.

Wechsler Intelligence Scale for Children-Revised and visual aural digit span test were performed to all of the patients before starting oxcarbazepine. The Denver Developmental Screening Test (DDST) was administered to only two patients younger than 6 years of age. The psychologic tests were assessed by the same person.

Oxcarbazepine was begun at the dose of 10 mg/kg/day and the dose was increased to 20 mg/kg/day and 30 mg/kg/day, respectively, at the second and third week. The dose was increased to 45 mg/kg/day if there was no seizure control. Exiting criteria were uncontrolled seizures even with this dose or untolerated side effects. Student t test and Kaplan-Meier estimates were used respectively to evaluate psychologic tests, laboratory parameters, and seizure-free period.

Results 

Of the patients, 33 (83.3%) had no seizure at the end of third month. Two patients had intolerable side effects that necessitated withdrawal of the drug. Five patients with partial epilepsy (three symptomatic, two idiopathic) and two patients with generalized epilepsy had seizure recurrence in the first 3 months and the dose was increased to 45 mg/kg/day. One patient with symptomatic partial epilepsy had two complex partial seizures and secondary generalized seizure even with this dose and excluded the study at the fifth month.

The other six patients had no seizure recurrence after the dose elevation. At the sixth month, two patients with partial epilepsy had four seizures and two patients with generalized epilepsy had two generalized tonic clonic seizures. One of them had irregular drug usage. Drug dose was elevated to 45 mg/kg/day in the other three patients. At the end of 6 months, 91.7% of the patients with generalized epilepsy, and 81.2% of the patients with partial epilepsy were seizure free. The results are provided in Table 2.

Table 2. Assessment at the third and sixth months*

		No.	Partial Response (%)	Seizure Free (%)	No Response
	Assessment at the third month
	Partial epilepsy	17	5 (29.4)	11 (64.7)
	Generalized epilepsy	25	2 (8)	22 (88)
	total	42	7 (16.7)	33 (78.6)
	Assessment at the sixth month
	Partial epilepsy	16	2 (12.5)	13 (81.2)	1 (%2.5)
	Generalized epilepsy	24	2 (8.3)	22 (91.7)	–
	total	40	4 (10)	35 (87.5)	1 (%2.5)

* Two patients in each group were excluded from the study because of intolerable side effects.

We evaluated the seizure-free period of the patients with Kaplan-Meier analysis and found that 82.5% of the patients had no seizures during the 6 months (Fig 1).

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Figure 1. Seizure-free patients during 6 months with the Kaplan-Meier method. At the end of 6 months, 82.5% of the patients were seizure free.

Electroencephalography studies were evaluated before and after therapy. General epileptic discharges (n = 15), generalized spike wave activity (n = 3), and focal spikes (n = 24) were observed. General epileptic discharges and generalized spike wave activity improved in 12 patients (66.6%), but only small fluctuations were observed in focal spikes at the end of 6 months.

Serum electrolytes were evaluated before and during therapy. Hyponatremia was not observed, although in two asymptomatic patients serum sodium levels were 132 mEq/L at the first month control. These results were in normal ranges at the third month control.

Serum cholesterol and low-density lipoprotein levels were in normal ranges in all patients but increased significantly 6 months after oxcarbazepine therapy. Triglycerides and high-density lipoprotein levels were unaffected before and after therapy. The results of laboratory parameters are provided in Table 3. Abbreviations: VADS=Visual aural digit span test WBC=White blood cell Two patients younger than 6 years of age were evaluated with the DDST and their results were unaffected before and after therapy. The results of the psychologic tests before and after therapy are listed in Table 3. Tolerable side effects included drowsiness (n = 12), weight gain (n = 5), dizziness (n = 4), headache (n = 4), aggressivity (n = 4), mild elevation of liver function tests (n = 1), rash (n = 1), and diplopia (n = 1). Five children with a mean age of 11.2 years had weight gain. Weight gain at the end of 3 months was 4, 2.6, 4.2, 4, and 2.5 kilograms, respectively, in these children. Severe headache and leukopenia were the side effects, which caused withdrawal of oxcarbazepine in two of the patients.

Table 3. Mean results of the laboratory parameters and psychologic tests before and after therapy

		Before Therapy (±S.D.)	After Therapy (±S.D.)	P
	Psychologic tests
	Oral score	93.7 ± 19.7	94.4 ± 19.6	0.2
	Performance score	92.28 ± 18.7	92.42 ± 19.1	0.765
	total	92.78 ± 18.2	93.4 ± 18	0.272
	VADS total score	21.7 ± 3.1	22.1 ± 3.8	0.24
	Laboratory parameters
	White blood cell count (/mm3)	7,860 ± 2,128	8,004 ± 1,961	0.796
	Hemoglobin (g/dL)	13 ± 1.1	13.2 ± 0.8	0.25
	Platelet (/mm3)	293,650 ± 59,587	274,600 ± 51,180	0.17
	Cholesterol (mg/dL)	157.2 ± 30.5	162.9 ± 27.5	0.041
	Triglyceride (mg/dL)	88.5 ± 34.4	93.2 ± 35	0.208
	HDL-cholesterol (mg/dL)	56.8 ± 19.5	56.8 ± 12.3	0.992
	LDL-cholesterol (mg/dL)	85.5 ± 29.4	92.8 ± 31.2	0.03
	Sodium (mEq/L)	138.8 ± 3.1	138.4 ± 3.3	0.69

Discussion 

Oxcarbazepine is an effective antiepileptic drug in both generalized and partial epilepsy. In a multicenter study with 229 adults and 31 children, it was reported that 73 patients did not benefit sufficiently, although 165 patients had seizure control [8].

It is reported that oxcarbazepine is as effective as phenytoin in monotherapy of newly diagnosed patients with generalized and partial epilepsy and has fewer side effects than phenytoin [9].

Gaily et al. [10] treated 53 children under 7 years of age with oxcarbazepine. Forty-three of these children had been intractable to one or more antiepileptic drugs, including carbamazepine, previously. Of the children with previous unsatisfactory carbamazepine treatment, 13% became seizure free and 43% had a reduction of seizures of at least 50%.

In a double-blind multicenter study, no significant difference in seizure frequency between oxcarbazepine and carbamazepine was reported, although oxcarbazepine caused significantly fewer side effects than carbamazepine [11].

Beydoun et al. [12] began oxcarbazepine 2,400 mg/day vs 30 mg/day monotherapy in 87 patients with partial epilepsy. Exiting criteria were a twofold increase in partial seizure frequency and occurrence of a single generalized seizure. The percentage of the patients meeting one of the exit criteria was significantly lower (P < 0.0001) for the oxcarbazepine 2,400 mg/day group (41%) than the oxcarbazepine 300 mg/day group (93%).

In an another trial, it was also reported that oxcarbazepine at 2,400 mg/day is well tolerated and efficacious when administered as monotherapy in patients with uncontrolled partial onset seizures [13].

Schachter et al. [14] compared 1,200 mg/day oxcarbazepine with placebo in a multicenter double-blind randomized placebo-control monotherapy trial. Of the patients in this study, four were excluded because of partial seizures, two patients were excluded with new-onset secondarily generalized seizures, two patients were excluded because of serial seizures, and two patients were excluded because of status epilepticus. The percentage of the patients who met one of the exit criteria and total partial seizure frequency during the double-blind treatment were statistically significant in favor of oxcarbazepine group. The authors concluded that oxcarbazepine administered as monotherapy is effective and safe for the treatment of partial seizures.

In our study, 81.2% of the patients with partial epilepsy and 91.7% of the patients with generalized epilepsy were seizure free at the end of 6 months.

Isojarvi et al. [15] reported that serum total cholesterol levels decreased although serum high-density cholesterol and triglycerides were unchanged in 12 male patients after replacing carbamazepine with oxcarbazepine. In contrast to these results, Papacostas et al. [16] reported on a patient who developed high serum cholesterol and low-density lipoprotein levels with both carbamazepine and oxcarbazepine, although the triglyceride and high-density lipoprotein levels were unaffected. In our study, serum lipid levels were all in normal ranges, but total serum cholesterol and low-density lipoprotein cholesterol levels were elevated statistically significant 6 months after oxcarbazepine therapy. Triglyceride and high-density lipoprotein levels were unaffected as in the previous study. We thought that lipid levels should be monitored in the next months of the therapy.

The most common adverse effects of oxcarbazepine are headache, drowsiness, weight gain, and nausea. Lipid elevation, leukopenia, hyponatremia, diplopia, and hypothermia are rare [17]. Oxcarbazepine has been associated with hyponatremia. It is usually mild and tended to increase at the higher doses. Gaily et al. [10] reported serum sodium levels below 132 mEq/L in seven of the 48 children, but only two of them were symptomatic. The authors suggested that the risk of symptomatic hyponatremia may increase when the child contacts an infection or has a prolonged seizure. In our study, serum sodium levels were 132 mEq/L only in two asymptomatic children at the end of 3 months.

The most common adverse effect was skin rash in a multicenter study with 260 patients [8]. The most common adverse effect was drowsiness in our study, but it was tolerated after 2 weeks of therapy. Leukopenia and severe headache were the adverse effects that lead to withdrawal of the oxcarbazepine.

The drug dose was 30 mg/kg/day in our study and elevated to a maximum of 45 mg/kg/day if there was no seizure control. The maximum child dose reported in literature is 123 mg/kg/day [18]. Gaily et al. [10] reported that young children need higher doses than adults.

At the outset, we aimed to evaluate efficacy and adverse effects of oxcarbazepine as monotherapy in children. In our study 87.5% of the patients were seizure-free at the end of 6 months. We believe oxcarbazepine is an effective and well-tolerated drug for childhood epilepsy.