Modern pharmacotherapy of epilepsy was heralded by the serendipitous discovery of the anticonvulsant properties of phenobarbital in 1912 by Alfred Hauptmann. Despite the development of successive generations of AEDs, phenobarbital has retained a unique position in the therapeutic armamentarium and is still the most widely prescribed treatment worldwide. Its advantages include reliability of supply, affordable cost, broad spectrum of action and ease of use (56). The drug also has disadvantages such as sedation, behavioural side-effects, enzyme induction and possible teratogenesis.
Another significant milestone in AED development was the introduction of phenytoin, the first non-sedating AED, in the 1930s as a result of systematic screening of compounds using novel animal models. A number of other AEDs have become available in the ensuing years, including carbamazepine, ethosuximide, primidone, valproic acid and some benzodiazepines. These agents are generally regarded as "old" or "established" AEDs. After a hiatus of nearly 20 years, there has been accelerated development of newer AEDs, with 10 compounds having been licensed globally since the late 1980s. These are in chronological order, vigabatrin, zonisamide, oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam and pregabalin. Although none of the modern AEDs has demonstrated superior efficacy to the established agents, they may be the preferred option for some patients as they are generally better tolerated and produce fewer drug inter actions. Whether their substantially higher cost is justified in the majority of people with epilepsy is open to debate.
AEDs differ in many important aspects including their efficacy against different seizure types (i.e. absence, myoclonus, partial, tonic-clonic, and atonic), their side-effect profiles (i.e. neurotoxicity, idiosyncratic reactions, long-term complications, and teratogenicity), their potential for pharmacokinetic interactions (i.e. enzyme induction, and inhibition), and their ease of use (i.e. titration and daily dosing). An AED should be selected to "match" the characteristics of the patient, such as his or her epilepsy syndrome, age, gender, co-existing illnesses and concomitant medication (57). When monotherapy has failed, there are insufficient data to guide the physician on how best to combine AEDs. Combinations with low risk of pharmacokinetic interactions should be preferred, and there is some evidence that the success of duotherapy can be improved by paying attention to mechanisms of action and using lower dosages (58).
Patients newly diagnosed with epilepsy should be started on a single AED, which will be effective in controlling their seizures in approximately 60% (41). Treatment may be safely withdrawn in some patients who have entered remission, particularly in children (59). There is still no consensus about the duration of remission before AED withdrawal should start. In children a period of six months has been advocated and in adults a period of at least two years. When two successive AEDs given as monotherapy have failed, most authorities would recommend combination therapy. Outcome studies suggest that after failure of two or three treatment schedules, the chance of subsequent remission with further drug manipulation is small. Between 30% and 40% of patients will continue to have seizures despite "optimal" AED therapy (48). These individuals with refractory epilepsy should be assessed for suitability of non-pharmacological management strategies, such as surgery, vagus nerve stimulation (VNS), or ketogenic diet.
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