Editorial Comment


  • AS Harvey

    1. Children's Epilepsy Program Department of Neurology Royal Children's Hospital, and Comprehensive Epilepsy Programme Austin Health, Melbourne, Victoria Australia
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 Dr AS Harvey, Director, Children's Epilepsy Program, Department of Neurology, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia. Fax: +61 3 9345 5977; email: simon.harvey@rch.org.au

The treatment of children with refractory epilepsy has advanced considerably in the last decade, with the release of several new anticonvulsant drugs, renewed interest in the ketogenic diet, increased application of epilepsy surgery and the development of vagal nerve stimulation. Since 1994, seven new anticonvulsant drugs have been approved in Australia: vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine and levetiracetam. Although each was approved on the basis of adult trial data, with indications initially limited to adjunctive treatment in older patients with partial seizures, most have since been shown to have efficacy in children with various seizure types, and at least lamotrigine has gained relatively wide acceptance by paediatricians.

Topiramate is a novel drug known to exert multiple anticonvulsant effects including sodium channel blockade, enhanced GABAergic transmission, carbonic anhydrase inhibition, glutamate blockade and possibly calcium channel blockade1. This range of in vitro pharmacological effects may, in part, explain the broad spectrum of anticonvulsant effects in animal models2 and clinical trials of epilepsy3−6, as well as the apparent lack of seizure exacerbation7 and the impression of greater efficacy relative to other anticonvulsant drugs8,9. Topiramate has been shown in randomized clinical trials to have significantly greater efficacy compared to placebo as adjunctive therapy in adults and children with refractory partial seizures5,6, generalized tonic-clonic seizures4 and major seizures associated with the Lennox−Gastaut syndrome3. Responder rates, seizure free rates and retention rates in these trials are generally higher than with many other anticonvulsants3,5,8,10−12. Topiramate has also been shown in randomized clinical trials to be effective with reduction to monotherapy and when used first-line in patients with new-onset epilepsy13,14. Small open-label studies in children with absence epilepsy15, severe myoclonic epilepsy of infancy16,17 and infantile spasms18 suggest some efficacy in these epilepsy syndromes.

However, a potential downside of a drug with multiple inhibitory effects on neuronal function is a tendency for neurological side effects. Adverse effects reported from clinical trials of topiramate include: sedation and tiredness, memory and concentration difficulties, dizziness and ataxia, behaviour disturbance, anorexia and weight loss, nephrolithiasis and paraesthesia3−6,13,14. Cognitive side effects of topiramate are frequently reported, with difficulties in verbal fluency being prominent19−23, yet these may be reduced or avoided with slower introduction, lower target dose and avoidance of concomitant medications19. Carbonic anhydrase inhibition from topiramate predisposes to a mild metabolic acidosis24,25 and hypercalcuria, mechanisms that are presumably responsible for the predisposition to paraesthesiae and nephrolithiasis, the latter being only rarely reported in children. Appetite suppression and weight loss (about 10% on average) associated with topiramate treatment may be desired effects for many adult patients with premorbid or drug-related weight gain, but they are of potential concern in children. Weight loss usually ceases after a few months on topiramate, and weight gain over time is reported in children on topiramate26,27; however, long-term data on height and weight velocity are lacking. With the potential for neurobehavioural side effects, appetite suppression, weight loss, metabolic acidosis and hypercalcuria, growth and developmental issues must be at least a theoretical concern and warrant clinical monitoring in children taking topiramate.

Meta-analysis of anticonvulsant trials suggests that topiramate is relatively less well tolerated than other new anticonvulsants8. In this issue of the Journal, Reith and colleagues28 highlight a relatively high rate of side effects in their experience with topiramate. Of 159 children commenced on topiramate, 30% developed a treatment limiting adverse effect in the first 2 years of treatment, neurobehavioural problems and weight loss being most common. Similar observations in paediatric settings have been made by other authors29,30, and although these studies are retrospective and uncontrolled, they serve to highlight potential side effects when such drugs are used in wider clinical practice.

Topiramate was initially licensed in Australia for use as adjunctive therapy in adults and older children with partial and generalized seizures. More recently, the indication has been broadened to include treatment in children down to the age of 2 years, conversion to monotherapy, and treatment of newly diagnosed epilepsy, the latter indication not being reimbursed via the Pharmaceutical Benefits Scheme1. The pharmacokinetic profile of topiramate is favourable with rapid oral absorption, high oral bioavailability, little plasma protein binding, linear pharmacokinetics with predominantly renal excretion and limited hepatic metabolism, a half-life suited to twice daily dosing (approximately 24 h in adults, 12 h in children, shorter in infants), and minimal drug interactions31,32. Drug formulation is in tablets and sprinkles that must be swallowed whole and immediately, due to the drug's unpalatable taste. Starting dose is generally about 1 mg/kg per day with fortnightly dose escalations ideally over approximately 8 weeks to a target dose of about 4−5 mg/kg per day (maximum dose 8−10 mg/kg/day). The paediatrician might recognize similarity with the titration of lamotrigine without valproate.

Topiramate is one of the most efficacious anticonvulsants available and, in the author's opinion, is the drug most likely to control seizures in a child with refractory epilepsy. However, the tendency to neurological side effects during titration and early maintenance, particularly when added to other anticonvulsants or escalated rapidly, may ultimately limit the therapeutic trial. Furthermore, while long-term seizure control is often maintained, concerns about diminished weight gain or cognitive development often demand re-evaluation of extended treatment. Whether topiramate is widely prescribed by paediatricians in Australia will likely depend on the balance achieved between efficacy and tolerability in their patients with refractory epilepsy.