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idiosyncratic (allergic) toxic interactions. The decision regarding which additional AED to use
is again dependent upon the seizure type/epilepsy syndrome and drug safety profile. Some
authors term this ‘rational polytherapy’. This ‘rationalisation’ may be determined theoretically
by the drug’s known (or postulated) mechanisms of action, or practically by following
clinicians’ experience of using certain drug combinations. Consideration must also be given to
whether the two AEDs act synergistically or antagonistically, in terms of both effectiveness
and safety. Examples of rational combinations are shown in Table 3 (in part this reflects the
authors’ personal practice). The simultaneous use of three (or more) AEDs rarely, if ever,
proves to be more effective than two drugs and will almost certainly result in increased side
effects and, by causing drowsiness and disturbing a normal sleep pattern, may paradoxically
exacerbate seizure control. Therefore there needs to be an extremely good reason for using
more than two drugs concurrently.

Also, it is unlikely that polytherapy with three AEDs will produce any additional, significant
and sustained control; however, polytherapy using three or more drugs will almost certainly be
associated with an increased risk and frequency of side effects, as well as toxicity due to drug
interactions. The only situation where three drugs are acceptable is during substitution, i.e. one
drug being introduced as another is withdrawn. Unfortunately, it is usually far easier to initiate
polytherapy than to terminate it.

It is tempting but perhaps rather naive to expect that any of the new AEDs, with recognised
and even ‘designed’ mechanisms of action, will necessarily offer a more rational or scientific
basis for using specific drug combinations in every patient.

Drugs available

The older and most commonly used medications in the treatment of childhood epilepsy are
sodium valproate and carbamazepine. Phenytoin and phenobarbitone, previously drugs of first
choice for most seizure types before the advent of carbamazepine and sodium valproate, are
no longer considered to be first, second or third-line drugs because of their relatively
unsatisfactory long-term safety profile. However, in certain situations they may still be
effective, but only when other drugs have ‘failed’ and where seizure control is the major  if
not only  priority. Further, they remain the first-line treatment in the acute management of
neonatal seizures in view of their parenteral availability and safety profile. The
benzodiazepines5 are also effective AEDs, particularly for generalised, but also for focal
seizures and some epilepsy syndromes. Their use may be restricted by acute toxicity, and the
development of tolerance or tachyphylaxis. For these reasons, benzodiazepines are rarely, if
ever, the initial AED, other than for infants and children with myoclonic seizures as the only
seizure type, when low-dose clonazepam or clobazam may be used as monotherapy.
Nitrazepam may be effective in suppressing infantile spasms, and particularly when these have
arisen as a consequence of neonatal hypoxic-ischaemic encephalopathy. Clobazam is also often
very effective as an add-on treatment for treating partial seizures (with or without secondary
generalised tonic-clonic seizures), atypical absences, electrical status epilepticus of slow-wave
sleep (ESESS) and catamenial seizures. Ethosuximide has traditionally been used for
childhood absence epilepsy, but can also be effective where spike-wave activity is prominent,
such as atypical absence of Lennox-Gastaut syndrome or continuous spike-wave of slow sleep.

Numerous AEDs are licensed for use in the UK as ‘add-on’ (adjunctive) or as monotherapy in
a range of seizure types and epilepsy syndromes  vigabatrin, lamotrigine, gabapentin,
topiramate, tiagabine, oxcarbazepine, levetiracetam, pregabalin, zonisamide, rufinamide,
lacosamide, eslicarbazepine and, most recently, perampanel. Lamotrigine has a monotherapy