It has long been recognized that seizures will be or will become refractory to pharmacotherapy in more than 30% of patients, and that localized related epilepsies are less likely to be controlled than the idiopathic generalized syndromes. Some of these patients will be offered epilepsy surgery or a vagal nerve stimulator. Many epilepsy sufferers will remain seizure-free on the first or second drug chosen. However, combinations of AEDs are usually prescribed in those unresponsive to monotherapy. The major dilemma inherent in this sequential approach of drug prescription lies in the imprecise understanding and definition of pharmacoresistance.

Ignorance of the neurobiological factors underlying the development of drug resistance in localizationrelated epilepsy leads to an inability to individualize the prognosis. Currently, crude outcomes in patients with identified causative pathologies, such as cortical dysplasia (CD) and mesial temporal sclerosis (MTS), which often but not always carry a poor prognosis, can only be guessed at. Indeed, evidence of MTS has been found in patients without seizures.

Pharmacoresistance may be regarded as the flip-side of epileptogenesis. Recent research has focused on the role of multidrug transport systems, most notably P-glycoprotein (P-gp), in the pathogenesis of refractory epilepsy. P-gp is an efflux transporter, encoded by the multidrug resistance (MDR1) gene, which contributes to the integrity of the blood brain barrier and actively extrudes a wide range of pharmacologic agents, including AEDs, from mammalian cells. Speculation suggests that overexpression of P-gp and other drug transport proteins in the region of epileptic foci can prevent AEDs from reaching their site of action. Elevated expression of these transporters has been reported in the region of both CD and MTS tissue. Whether drug transporters represent the cause or effect of recurrent seizures is unclear and perhaps unimportant given that experimental seizures can induce their expression and potentially reinforce inherent or acquired intractability.

AEDs
In the past decade, nine new AEDs have been licensed, substantially widening physicians choice, and the number of possible combinations is now almost limitless. However, there remain a number of issues to be addressed the number of trials of single AEDs that should be employed before the patient is treated with duotherapy, the number of AEDs, either singly or in combination (and in how many combinations), that need to fail before the seizure disorder can be recognised as refractory and surgery considered, the stage at which epilepsy becomes pharmacoresistant to AED treatment and what determines success or failure with AED therapy, and whether there are clinical features that will allow prediction of subsequent refractoriness . Responses and solutions to these issues depend on an understanding of the natural history of treated epilepsy.

Natural History of Treated Epilepsy
There are two classes of epilepsy patient easy compared with difficult-to-control . A long-term outcome study supports the hypothesis that patients with newly diagnosed epilepsy comprise two distinct populations. Approximately 60% have a good prognosis.They will become seizure-free on a modest or moderate dose of the first- or second-choice AED as monotherapy without developing intolerable side effects. Some of these will remain in remission after withdrawal of AED therapy. The other 30% to 40% have difficult-to-control epilepsy. These patients often have an underlying structural cerebral abnormality. They are more likely to have had a high number of seizures before treatment was initiated, a feature recognized increasingly as the result rather than the cause of the pathophysiological changes that later manifest as refractory epilepsy. Pharmacoresistant epilepsy may, therefore, be present de novo as well as evolving over time, and can be identified early when treatment with the first well-tolerated AED fails. Between these two subsets, there is a gray zone of patients who will respond to combination therapy.