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and doses of this particular therapy and there is as yet no established or universally accepted
mechanism of action.

Which drug?

Drug choice in childhood epilepsy should, wherever possible, be evidence based as in older
individuals. However, there are few randomised controlled trials on which to base drug choice
within the epilepsy syndromes. This in part reflects the logistical and ethical difficulties as well
as the expense in conducting paediatric trials. Nevertheless, the principal should still be to try
and base treatment strategies on robust evidence. The EMA has recently revised guidelines on
the development of AEDs in children. They state that focal epilepsies in children older than
four years of age have a similar clinical expression to focal epilepsies in adolescents and adults.
In refractory focal epilepsies, the results of efficacy trials performed in adults could to some
extent be extrapolated to children, provided the appropriate dose and safety data are
established. In children under four years of age, short-term assessment of response by using
video-EEG monitoring may be sufficient once efficacy has been demonstrated in older
children. For syndromes limited to childhood, sufficient experience needs to be gained in this
population before a new medicinal product may be registered for these indications in children56;
predictably such experience is likely to be largely anecdotal unless data can be obtained from
well-conducted national or international randomised controlled trials.

Many studies are conducted on the basis of seizure type rather than syndrome, are limited in
duration and reveal little in the way of long-term effects. The HTA (in 2004) suggested that
older drugs such as sodium valproate or carbamazepine should be used as first line over and
above newer anticonvulsants unless there was a contraindication57. The NICE guidelines for
the diagnosis and management of epilepsy in primary and secondary care, originally published
in 2004, underwent a pharmacological review in 201212. These took a GRADE approach to
evaluating evidence and guidance produced was based also on the cost effectiveness of AED
use.

Many paediatric epilepsies and epilepsy syndromes are associated with generalised seizures,
and for these the current drug of choice (at least in the UK) is usually sodium valproate. This
was confirmed by the SANAD (Standard and New Antiepileptic Drugs) study, which showed
sodium valproate to be superior in the treatment of generalised seizures over topiramate and
lamotrigine where sodium valproate would have been the physicians’ choice (arm B). Many of
the individuals in this study had genetic generalised epilepsy58. Further, a recent randomised
double-blind trial in the treatment of childhood absence epilepsy comparing ethosuxuimide,
sodium valproate and lamotrigine showed superior efficacy of sodium valproate and
ethosuximide over lamotrigine, but some neuropsychological advantage to ethosuximide59.
There has been increasing concern about the effect of sodium valproate on the unborn child of
mothers taking the medication – both an increased risk of malformations, as well as cognitive
delay in later childhood. For this reason the medication is not recommended as first line in girls
of child-bearing age, and when considered, the risks of taking the medication need to be
weighed against the risk of the epilepsy itself in each individual.

Epilepsies associated with focal seizures are slightly less common in children in contrast to
adults and for these individuals carbamazepine is the usual preferred treatment. Data from the
SANAD study60 arm A where carbamazepine would have been physicians’ choice
demonstrated that lamotrigine was at least as effective and associated with fewer adverse side
effects than carbamazepine, oxcarbazepine, topiramate and gabapentin. Although SANAD was
inclusive of children in the protocol, few children were recruited to this arm, and in the majority