Effectiveness of clobazam as add-on therapy in children with refractory focal epilepsy

Eficácia do clobazam como terapia adjuvante em crianças com epilepsia focal refratária

Effectiveness of clobazam as add-on therapy in children with refractory focal epilepsy

Eficácia do clobazam como terapia adjuvante em crianças com epilepsia focal refratária

Mariana Ribeiro Marcondes da Silveira; Maria Augusta Montenegro; Renata Cristina Franzon; Carlos A.M. Guerreiro; Marilisa M. Guerreiro

Department of Neurology, State University of Campinas, Campinas SP, Brazil (Unicamp)

ABSTRACT

The objective of this study was to evaluate the safety and efficacy of clobazam in children with refractory focal epilepsy. We investigated 100 consecutive patients concerning etiology of epilepsy, previously used antiepileptic drugs, seizure frequency and adverse events. Clobazam was introduced as add-on therapy in patients with previous failure of at least two monotherapies. Mean age was eight years-old and 39 patients were girls. Clobazam mean dosage was 23.6 mg/day. Mean use of clobazam was 18.6 months. Twenty-two patients had adverse events. Twenty-six patients became seizure-free, 11 had an improvement of >75% and in 58 there was no modification in seizure frequency. Five patients had an increase in seizure frequency. Clobazam efficacy lasted for more than one year in 42% of the seizure-free patients. Clobazam seems to be safe and effective in the treatment of focal epilepsy in childhood and should be considered in patients with refractory seizures.

Key words: clobazam, focal epilepsy, childhood.

RESUMO

O objetivo deste estudo foi avaliar a segurança e eficácia do clobazam em crianças com epilepsia focal refratária. Nós investigamos 100 pacientes consecutivos em relação à etiologia da epilepsia, uso prévio de drogas anti-epilépticas, freqüência de crises e eventos adversos. Clobazam foi introduzido como terapia adjuvante em pacientes que não responderam a pelo menos duas monoterapias. A idade média foi 8 anos e 39 pacientes eram do sexo feminino. A dose média de clobazam foi 23,6 mg/dia. O uso médio de clobazam foi por 18,6 meses. Vinte e dois pacientes tiveram eventos adversos. Vinte e seis pacientes tornaram-se livres de crises, 11 tiveram melhora > 75% e em 58 não houve modificação na freqüência de crises. Cinco pacientes tiveram aumento na freqüência de crises. A eficácia do clobazam permaneceu por mais de um ano em 42% dos pacientes sem crises. Clobazam parece ser seguro e eficaz no tratamento de epilepsia focal na infância e deve ser considerado em pacientes com crises refratárias.

Palavras-chave: clobazam, epilepsia focal, infância.

In childhood, most epileptic syndromes are benign. Nevertheless, there is a group of severe epilepsy syndromes with refractory seizures that do not respond well to the usual antiepileptic drugs (AEDs).

Clobazam, a 1,5-benzodiazepine with good efficacy and tolerance, is considered an excellent option as add-on therapy for adults with refractory epilepsy^1-9. Only a few studies have systematically investigated the efficacy and safety of clobazam in children^10-13.

The objective of this study was to evaluate the safety and efficacy of clobazam as add-on therapy in children with refractory partial epilepsy.

METHOD

This was a retrospective study, conducted at the pediatric epilepsy clinic of our university hospital. We evaluated 100 consecutive patients who met all the inclusion criteria, from June 2003 to February 2004. Patients were interviewed by one of the authors according to a semi-structured questionnaire that included the etiology of epilepsy, previously used AED, seizure frequency and adverse events. We collected data from the patients' routine visits and clinical files. The protocol and the informed consent were approved by the ethical committee of our university hospital.

Inclusion criteria were: age between six months and 18 years-old; diagnosis of focal epilepsy according to the International League Against Epilepsy syndrome classification¹⁴; previous failure of at least two monotherapies; use of clobazam as add-on therapy; signature of informed consent by parents or legal guardian.

Exclusion criteria were: diagnosis of generalized epilepsy or epileptic encephalopathy even if the patient also presented with focal seizures; progressive metabolic disorders or brain tumors.

Patients underwent interictal electroencephalographic (EEG) routine recordings using the International 10–20 System for electrode placement. Long term EEG monitoring was performed when appropriate.

Introduction of clobazam – Clobazam was introduced as add-on therapy (starting with 5 mg/day) in patients with previous failure of at least two monotherapies. The titration rate was according to clinical response, but the interval of increasing doses was no shorter than one week. The dose escalation was 5 mg for each step. The initial dose was 5 mg/day at bedtime, up to 60 mg/day, twice a day. Clobazam was prescribed on a minimally effective, up to the maximum, tolerated dose basis. Clobazam's dose was decreased or the drug was stopped if the patient presented with an adverse event.

Analysis of the data – For analysis of the results, patients were divided in four groups according to seizure control: a) seizure free; b) > 75% of seizure reduction; c) no improvement; and d) increase in seizure frequency.

In the group of patients with improvement in seizure control, we also assessed the duration of seizure reduction according to four categories of improvement: a) more than one year; b) six months to one year; c) three months to six months; and d) less than three months.

We performed an analysis curve, using the method of Kaplan and Meier, for retention of clobazam during the 18-month period.

Adverse events were analyzed according to the clobazam dosage and number of AEDs. We also analyzed adverse events in relation to the age of the patients. For both analyses we used the t-student test with the level of significance of 0.05.

RESULTS

Ages ranged from one year to 18 years old (mean = eight years old). Thirty-nine patients were girls. All patients, except one, were using at least one AED when clobazam was introduced: 40 with carbamazepine, 24 with valproate, 19 phenytoin, 12 phenobarbital, 11 lamotrigine, eight topiramate, seven oxcarbazepine, and one vigabatrin.

The Table shows the characteristics of the patients. Sixty-five patients had a symptomatic epilepsy syndrome. In 35 patients the etiology of seizures could not be established. An EEG showed epileptiform abnormalities in 85% of the patients.

Doses ranged from 5 to 60 mg/day (mean = 23.6 mg/day), and patients used clobazam for a period ranging from 0.5 to 78 months (mean = 18.6 months). Clobazam was discontinued when the maximum tolerated dose was reached without seizure improvement or due to adverse events.

Twenty-two patients presented adverse events: somnolence in nine, irritability in nine, headache in two, and allergic reaction, vomiting and ataxia in one patient each. In 11 patients the adverse events were mild or transitory; however, in 11 patients clobazam was withdrawn due to the severity of the adverse events, primarily irritability.

The mean dosage used by patients presenting adverse events was 21.542 mg of clobazam, as opposed to 24.276 mg in those without adverse events (p= 0.435). The mean number of AEDs used by patients presenting adverse events was 2.292, as opposed to 2.237 in patients without adverse events (p=0.635).

When adverse events were analyzed according to age, our data showed that irritability occurred mainly in pre-school age children (mean age = 5.7y) while somnolence occurred mainly in adolescents (mean age = 11.8y, p=0.005, Fig 1).

Twenty-six patients became seizure-free, 11 had >75% of seizure reduction and in 58 there was no modification in seizure frequency after introduction of clobazam. Five patients presented an increase in seizure frequency. It is important to note that in 42% of the seizure-free patients and in 36% of the patients with >75% seizure reduction, clobazam efficacy lasted for more than one year.

The Kaplan-Meier survival analysis revealed a retention rate of clobazam at 18 months (Fig 2).

Seizure-free patients – Twenty-six patients became seizure-free after introduction of clobazam as add-on therapy. Twenty-one patients had symptomatic epilepsy - eight focal cortical dysplasia, three focal atrophy, three hippocampal atrophy, two schizencephaly; and porencephalic cyst, diffuse atrophy, calcification, polymicrogyria, and vascular lesion in one patient each. Five patients had probable symptomatic epilepsy syndrome.

Patients with lower seizure frequency showed a sustained response to the treatment (p=0.021). Seizures were controlled for more than one year in 11 patients with weekly or monthly seizures, and only in one patient with daily seizures.

DISCUSSION

Clobazam has an important antiepileptic effect and is less expensive than the new AEDs, but still has not been considered as a first-line drug in the treatment of epilepsy³. In children, clobazam has equivalent efficacy to carbamazepine and phenytoin in monotherapy¹⁰. Clobazam has also been used for severe epileptic encephalopathies of childhood, such as Lennox-Gastaut syndrome, severe myoclonic epilepsy of infancy and electrical status epilepticus of sleep^15-18.

The definition of refractory epilepsy remains controversial; however, the chances of seizure control after the failure of two drugs are not good^19,20. In spite of this, 26% of the patients became seizure free after the introduction of clobazam and, in 42% of them, seizure control lasted for more than one year.

The retention of clobazam over a period of 18 months was more than 60% (Fig 2). Retention rate is a good marker for the comparative roles of efficacy and tolerability of AEDs. A recent review showed that clobazam is the only AED with a consistency of data in clinical practice²¹.

The major drawback of our study is the fact that the information was assessed retrospectively and there is no control group. Retrospective studies always include the possibility of bias that cannot be controlled or accounted for.

Although randomized controlled trials are considered the best proof of efficacy of a drug, add-on trials enable the study drug and co-therapy to be adjusted as needed, which mimics clinical practice. Moreover, they are accepted by regulatory agencies and enable a longer study duration²². Clobazam was withdrawn in 11 patients due to adverse events, mainly irritability and somnolence. It seems to be a safe drug, however, and its cognitive and behavioral effects are comparable to those of standard monotherapy in school-aged children²³. Similar to adults, in whom somnolence is the main adverse effect associated with clobazam, in our study, adolescents who had an adverse event presented mainly somnolence. As opposed to adults and adolescents, behavioral disturbances are frequently seen in children¹³, and this is in keeping with our data as irritability was the main finding seen in small children. Although 22% of the patients presented adverse events, when there was an improvement in seizure control most families accepted mild or transitory side effects.

Like most AEDs, increasing clobazam dose is usually ineffective when seizure control relapses²⁴. However, after a previous period in which it has been effective, clobazam may keep its antiepileptic effect when used intermittently²⁵.

Although tolerance to clobazam may occur, sustained responders have been identified. It is estimated that 28% of patients will have a long-term benefit without tolerance²⁴. Patients with a short duration of epilepsy and higher serum levels of clobazam tend to maintain their seizure control for longer periods^2,26. Unfortunately, we could not assess clobazam serum levels; however, we could identify sustained responders to clobazam as those with a lower seizure frequency. This is a small sample and larger series should be assessed in order to confirm our findings.

We conclude that clobazam seems to be safe and effective as add-on therapy for children with refractory partial epilepsy.

Received 21 March 2006, received in final form 1 June 2006. Accepted 24 June 2006.

Supported by FAPESP Grant # 03/00947-6.

Marilisa M. Guerreiro, MD - Department of Neurology, FCM / Unicamp - PO Box 6111 - 13083-970 Campinas SP - Brasil. E-mail: [e-mail]

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Publication Dates

• Publication in this collection
  11 Oct 2006
• Date of issue
  Sept 2006

History

• Received
  01 June 2006
• Accepted
  24 June 2006