Topiramate in the Treatment of Myoclonic-Astatic Epilepsy in Children: A Retrospective Hospital Audit
BACKGROUND: Myoclonic-Astatic Epilepsy (MAE) usually starts before five years of age and is associated with very frequent seizures and is highly resistant to treatment. AIM: To investigate the outcome of adjunctive topiramate (TPM) therapy in children with a diagnosis of MAE syndrome. Subjects AND METHODS: In an outpatient setting, case notes of 27 children who received TPM were retrieved and analysed. RESULTS: Records of 6 children with MAE, who were experiencing 2-8 atonic seizures daily before starting TPM were studied. Improvement was noted after addition of TPM (mean dose at steady-state 7.4±2.5mg/kg/day) to the regimen of 1-3 anti-epileptic drugs they were receiving concurrently. All but one child improved following the titration period: one had 50-80% improvement in the frequency of atonic seizures and three had over 80% improvement. However, one child who showed over 80% improvement and was free of atonic seizures, later developed increased frequency of other seizure types. In one child there was no significant improvement. Improvement has been sustained for over 6 months in three patients and over 4 months in one; three have continued TPM. TPM was stopped in three patients (reduction in seizure control/no improvement). CONCLUSIONS: This study supports the efficacy of TPM in controlling atonic seizures in MAE and indicates that it should be considered as an add-on drug in the management of this ‘difficult-to-treat’ epileptic syndrome.
Myoclonic-astatic epilepsy (MAE) usually starts during the first five years of life and is generally associated with poor long-term outcome. The most prominent seizure type is a drop attack, which may be preceded by a series of myoclonic jerks. This type of epilepsy is associated with very frequent seizures, great morbidity, particularly related to injury from falls, and resistance to treatment.
The objective of the study was to investigate the outcome of adjunctive therapy with the anti-epileptic agent topiramate (TPM) in children with a diagnosis of MAE syndrome attending an outpatient clinic. MAE was defined as a primary generalised epilepsy with myoclonic, atonic and other types of seizures, including non-convulsive status, generalised tonic-clonic seizures or febrile seizures, rare or absent tonic attacks and a preponderance of fast spike-wave or polyspike-wave complexes on the electroencephalogram.
This was a retrospective, open-label study. Case notes of children receiving topiramate (TPM) for treatment of epilepsy while attending the Department of Child Health, University Hospital of Wales from February 2001 to February 2002 were retrieved and analysed. The group of patients included 27 children (16 boys, 11 girls) with ages ranging from 3.0 to 17.3 years (mean age, 9.4 years). According to the International Classification of Epilepsy and Epileptic Syndromes (ICE) of 1989,3 ten seizure types were identified, with 11 children also having a syndromic diagnosis. The diagnosis was made by a paediatric epileptologist after clinical examination and review of electroencephalograms.
Children with MAE and treated with TPM were selected from the group. The details about the age at which each of these children began treatment with TPM, their TPM maintenance dosage, seizure frequency before and after TPM treatment, and the duration of effect in reducing seizures (to date) were recorded. Seizures were carefully documented in the diaries that were maintained by well-informed caregivers, and children were followed up in an outpatient clinic every two to four weeks by two paediatric neurologists. During the period of TPM administration, their treatment regimen remained unchanged.
Twenty-seven children (16 boys, 11 girls) with age ranging from 3.0 to 17.3 years (mean age, 9.4 years) were receiving TPM. Complex partial seizures with secondary generalisation and atonic seizures (nine children each) were the most frequently encountered seizure types. The other seizure types that were noted included primary generalised tonic-clonic seizures (3), partial seizures with secondary generalisation (1), myoclonic (5), tonic (3), absence (6), absence with eyelid myoclonia (1), and non-convulsive status epilepticus and multiple seizure type (5 each). Epileptic syndromes that were diagnosed included MAE (6), Lennox-Gastaut (2) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), childhood absence epilepsy (CAE), continuous spike-waves of slow sleep (CSWS, electrical status epilepticus in sleep) in one each. The predominant seizure type and treatment characteristics of 6 children with MAE (4 boys and 2 girls) are shown in [Table - 1] and [Table - 2]. The mean age of the children with MAE was 7.0 ± 2.9 years. All patients presented with atonic seizures and myoclonic seizures, and two with other seizure types including generalised tonic-clonic seizures, absence seizures and episodes of non-convulsive status epilepticus. They experienced from 2-8 seizures daily before starting treatment with TPM. The children had been previously treated with an average of 4 (range 1-8) anti-epileptic drugs (AEDs) (not always concurrently) before TPM was added to their treatment regimen. TPM was not used as a first-line medication in any child but was used as the second, third or fourth adjunctive AED (median, 3).
When TPM was added to their treatment regimen, the group concurrently took between 1 and 3 other AEDs; five children were on lamotrigine, four on valproate and four on clonazepam. Their average TPM dose at steady state was 7.4 ± 2.5mg/kg/day. Previous to this, one patient had been taking prednisolone, two had been on vigabatrin and one patient had been taking carbamazapine.
From records documented by each child's caregiver, all but one child improved following the titration period: one had a 50-80% (67%) improvement in the frequency of atonic seizures; three had over 80% improvement. One child, who showed complete cessation of atonic seizures, later developed increased frequency of other seizure types. In another child there was no significant improvement. Improvements were sustained for over six months in three of these patients and for four months in one; three of these patients continued TPM therapy. No apparent relationship was determined between response and seizure type, titration schedule, or maintenance dose.
Treatment with TPM was stopped in three patients; two of these showed a reduction in seizure control - one with an increase in atonic seizures and one with an increase in other seizure types. One child showed no improvement. TPM was not stopped in any child due to the side-effects of the treatment, although three children experienced them. These were recognized side-effects of TPM therapy and included CNS effects (drowsiness, lethargy) and gastrointestinal symptoms (anorexia, weight loss), which were mild, transient and occurred during titration, except for one case of minor weight loss that persisted longer [Table - 3].
It was interesting to note that in our group of children on TPM there were two children with the Lennox-Gastaut syndrome. Neither responded well to TPM. In particular, there was no notable improvement in the frequency of atonic seizures in these two children.
This communication reports a retrospective hospital audit of children with MAE who were treated with TPM. Although randomised, double-blind, controlled studies are the 'gold standard', such open-label studies do provide some information regarding the usefulness of treatment and are of greater significance when they report on its use in special groups (such as children) in whom controlled trials are difficult to initiate.
Sodium valproate is the most commonly used anti-convulsant for the treatment of myoclonic epilepsies including MAE. Carbamazepine has been reported to aggravate myoclonic seizures,,, and appears to have the stronger aggravating potential in patients with juvenile myoclonic epilepsy when compared with phenytoin. Recent evidence indicates that lamotrigine is inappropriate in severe myoclonic epilepsy in children as it increases the frequency of seizures. Gabapentin, oxcarbazepine, vigabatrin and tiagabine are also reported to exacerbate myoclonic seizures., However, stiripentol may have a role in the treatment of severe myoclonic epilepsy in infants, and seizures of progressive myoclonic epilepsies may respond to zonisamide, although the general experience of this agent is limited.
TPM is a potent anti-epileptic drug with multiple mechanisms of action and a broad spectrum of activity. It has been used for adjunctive therapy of partial onset seizures and may also be effective as monotherapy in adults for this type of seizure.,, TPM has also been shown to be effective as adjunctive therapy in children with partial onset seizures, primary generalised tonic-clonic seizures, Lennox-Gastaut syndrome and in the treatment of infantile spasms. More recently, TPM therapy has been observed to be beneficial in 18 patients aged between 2 and 22 years with severe myoclonic epilepsy refractory to various other agents. Three patients became seizure-free, and ten had over 50% reduction in seizure-frequency while six achieved a reduction of greater than 75%.
Our experience in this small group of six children with MAE shows that TPM therapy can result in a reduction in the frequency of atonic seizures. On an intent-to-treat basis to continue and maintain children on TPM, there was a sustained improvement in 50% of the children. There are hardly any studies reporting about the efficacy of TPM in myoclonic epilepsy in infants. In a study of 18 subjects aged between 2 and 22 years (11 subjects were under 16 years), Nieto-Barrera et al observed that 16% of subjects became seizure-free and 72% showed a reduction in seizure rate. There is no published data focusing only on the use of TPM in MAE. In a prospective study, Mikaeloff et al enrolled 207 children with epilepsy who were receiving TPM. Four of these were children with MAE. The study reported that all responded to treatment, and one child became seizure-free. In our group of children on TPM there were two children with the Lennox-Gastaut syndrome. Neither responded well to TPM, in particular, there was no notable improvement in the frequency of atonic seizures in either child. This experience was similar to that of Mikaeloff et al where the response rate to TPM was mild in the Lennox-Gastaut syndrome in comparison to a good response in MAE amongst other epilepsy syndromes. 
In our study, two children showing a reduction in seizure frequency had been treated previously with carbamazepine and vigabatrin, which are known to exacerbate myoclonic seizures. Reductions in seizures cannot be attributed to their discontinuation, as they were not stopped during titration of TPM dose. One child had episodes of non-convulsive seizure epilepsy before starting TPM and, although none were recorded during the eight months of follow-up, this may not reflect the effect of TPM alone.
The findings of this open-label retrospective study further support the efficacy of TPM in MAE, and indicate that it should be considered in the management of this difficult-to-treat epileptic syndrome.