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REVIEW Antiepileptic drugs: safety in numbers?

Epilepsy is a common neurological condition, with a lifetime prevalence of between 2% 1, 2 and 5%3 of the general population, and a point prevalence of between 4 and 80 per 1000 4. So common is it among all races that epilepsy may be viewed, not as a rare curse on the individual, but as an all-too frequent price that man and other vertebrates pay for maintaining a plastic and adaptable central nervous system. Within the first few years of the next century, some estimates suggest that there will have been 11 new antiepileptic drugs (AEDs) licensed for use as either add-on or monotherapy since the late 1980s 5. Despite these recentwelcome additions to the ranks of available anticonvulsants 6 epilepsy remains both stigmatizing and debilitatingfor many of those with the disorder 7. Are there grounds for optimism about the possibility of treating refractory epilepsy? Previous studies have shown that around one-third of patients will remain refractory to anticonvulsant monotherapy with the established drugs 7, 8. Given this, the new drugs have, with justification, generated a great deal of interest, but despite their use most clinicians would admit that a significant number of patients with epilepsy have seizures that remain unsatisfactorily controlled9. The challenge for epileptologistsover the coming decades is to further reduce the size of this population with refractory disease. The new generation of AEDs are undoubtedly an advance in the treatment of epilepsy (given their advantages of increased tolerability 6, 10 and a decreased tendency to cause pharmacokinetic interactions 11), but it could be argued that a continued search for more new anticonvulsants is an inefficient way of helping our patients. Perhaps it would be more fruitful to look for better ways of using the drugs already at our disposal. For many different conditions in many different specialties, the use of drug combinations is the rule rather than the exception. Admittedly, anticonvulsants are potentially neurotoxic 8, can result in severe systemic reactions4, and have the tendency to sustain multiple pharmacodynamic and pharmacokinetic interactions12. The same, however, is true of antiparkinsonian drugs13, and monotherapy would never be advocated asthe ideal management strategy for the treatment of Parkinson’s disease 13. In fact here the opposite philosophy applies, where a rational combination of compounds is used at an early stage in an attempt to delay symptomatic progression 13. Since the 1970s, in contrast, anticonvulsant monotherapy has long been regarded as the ideal management strategy. A series of studies by Shorvon and Reynolds14–16 argued against AED polypharmacy on thebasis of its strong association with adverse events, they felt, with little evidence of an increase in efficacy. While it seems axiomatic that newly diagnosed epilepsy should be treated with a single drug, the didacticism in favour of monotherapy fails to recognize the realities of everyday practice. One survey has shown17 that even when under review by specialist epilepsy services, almost half the patients required (or, at least, were receiving) long-term treatment with anticonvulsant polypharmacy. At present, even taking into account those compounds currently undergoing phase three testing, it seems unlikely that any of the new AEDs will, by themselves, prove to be the ‘magic bullet’ for epilepsy. In a medical climate so keen on evidence guiding our medical management, it therefore falls to us as epilepsy specialists to formulate a rational strategy for its treatment. Sadly, though, it seems pre-