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Combined therapy and second-line anti-absence drugs
Selection of drug combination is again based on the clinical pattern principle.

Lamotrigine. More than half of patients with valproate-resistant absences may become seizure
free with add-on lamotrigine70. This combination is also highly effective with regard to
myoclonic seizures and GTCS (Table 3). The effect is probably mediated through inhibition of
lamotrigine metabolism by sodium valproate, and can be best achieved by escalating the dose
of lamotrigine according to clinical response and not to the recommended upper ‘therapeutic’
doses70. The drug has been used in children with myoclonic absences with good results37.
Anecdotal evidence suggests that a favourable response on substantial dose of sodium valproate
combined with a low to moderate dose of lamotrigine may be lost if lamotrigine is further
increased and substitution of sodium valproate is attempted. This combination may augment the
risk for allergic skin reaction, and may rarely provoke other adverse immune responses71.

Ethosuximide. The addition of sodium valproate to ethosuximide may double serum
concentration of the latter with concomitant toxicity72. Conversely, the addition of ethosuximide
may reduce serum level concentration of sodium valproate. Bearing this interaction in mind, the
combination of sodium valproate and ethosuximide may be helpful in managing refractory
absences65, and is probably the first-line treatment of myoclonic absences36.

Clonazepam is considered the most effective anti-absence benzodiazepine and the most
powerful drug against myoclonic jerks, with a good effect on GTCS73,74. It may also be
effective in photosensitive epilepsy75. However, because of its potential to cause sedation and
the problem of tolerance76, it is usually prescribed as a second-line adjunctive therapy (Table
3). Other adverse effects include fatigue and disturbance of coordination and, less commonly,
agitation, confusion and aggressiveness. It is also useful to remember that its combination with
sodium valproate during pregnancy may amplify the risk for teratogenicity60. Rapid
discontinuation should be avoided.

Acetazolamide has a clear anti-absence effect77, and may also be useful in JME78. Tolerance
frequently develops but a period of withdrawal may restore its efficacy. Renal calculi are
consequent to its carbonic anhydrase activity and together with rare but severe serious
idiosyncratic reactions associated with sulfonamides (rash, aplastic anaemia, Stevens-Johnson
syndrome) limit its use as an adjunctive treatment.

Levetiracetam can be effective as monotherapy in JME and other IGE sub-syndromes, and
can suppress photosensitivity in combination or monotherapy79,80.

Contraindicated AEDs

Antiepileptic drugs (AEDs) may aggravate pre-existing seizures or induce new seizure types,
and such an effect may be either idiosyncratic or syndrome/seizure-related. Factors that
hamper the identification of such AEDs include incorrect syndromic and seizure diagnosis,
the natural fluctuation of seizure frequency and severity, and the fact that most drug trials are
not based on a syndrome and age-specific approach, nor are they designed to detect seizure
worsening. Inevitably, most of the existing information on seizure aggravation relies on
clinical observations on small series and case studies, and for some drugs such evidence is
more convincing than for others. Knowing the drugs that can aggravate idiopathic generalised
epilepsies with absences is particularly important as the vast majority have a favourable
prognosis.

Carbamazepine81, vigabatrin82, tiagabine83 and gabapentin84 are contra-indicated in the
treatment of TA irrespective of cause and severity. However, carbamazepine may be helpful
in controlling GTCS84. As GABAergic substances, vigabatrin, tiagabine and gabapentin are