Identification of pharmacoresistant epilepsy.

Until relatively recently, the epilepsy literature regarding seizure prognosis has been divided between epidemiological studies of remission and studies focused upon experimental pharmacological therapies and surgical treatment of refractory epilepsy. In the first case, the epidemiological studies were not specifically interested in pharmacoresistance. At best, there was a tacit assumption that not being in remission was the complement of pharmacoresistance. Hence, by studying remission, one was, for all intents and purposes, studying pharmacoresistance. In the second case, experimental and surgical therapies were targeted to patients who were clearly refractory to standard pharmacologic treatments. The fact of pharmacoresistance was established well before patients entered such treatment studies. The pertinent questions regarded whether a new approach could offer any hope where the standard ones had already clearly failed. These studies offer no clear definition of intractability. In the case of epidemiological studies, defining pharmacoresistance is irrelevant to the outcome. Remission is defined as the absence of seizures 1,21,22,34,47, and the reason for not being in remission is immaterial. For studies of surgical therapy and randomized trials of new drugs, the definition is also not especially relevant as patients treated in these settings are selected to be some of the most extreme cases in whom no doubt remains regarding their seizures’ resistance to therapy. For example, in one surgical study, the median number of different AEDs tried prior to referral for surgery was five 7. In very broad and general terms, pharmacoresistance is the failure of seizures to come under complete control or acceptable control in response to AED therapy. Different specific conceptual definitions have been summarized previously 2. In theory, one could require that all possible drugs in all possible combinations be used in order to determine this 29. Practically, this is an impossible standard to meet and likely dangerous for patients as well. This leaves important questions regarding how best to define pharmacoresistance in a way that it can be meaningfully studied. To date, only a few studies have defined pharmacoresistance separately from lack of remission 1,9,14,17,18,27,37,57. In these definitions, common elements are a) the number of drugs that need to be failed, b) the seizure frequency, and c) factors related to time (Table 1). The consensus regarding number of drug failures appears to be two or three. For other aspects there is somewhat greater variability. Some require a specified period during which a minimum seizure frequency is observed. Others require that a seizure have occurred within a specified period of time (e.g. the last six months). The absolute agreement among these various definitions tended to be high (83–96%), although agreement corrected for chance (Kappa) ranged from a low of 0.35 (poor) to a high of 0.79 (excellent)6. Table 1 Components of selected definitions of pharmacoresistant or intractable epilepsy. Many of the definitions are designed for identifying the prevalence of pharmacoresistance at a given point in time (e.g. two years after diagnosis 27, five years after diagnosis 1 or as of last contact 17). Prevalence is a useful concept in epidemiology and public health. It provides an estimate of the number of individuals at a specified point in time who have a specific condition. The prevalence of intractable epilepsy in a geographically defined population in France was recently estimated using two slightly different definitions to determine the number of people in the population who met each definition and the proportion of people with epilepsy who were pharmacoresistant 53. Both definitions required the failure of two AEDs. Defining intractability as any seizure in the past year yielded a population prevalence of 1.4/1000 and accounted for 26% of people with epilepsy. The second definition required an average of 1 seizure/month during the past year and yielded a population prevalence of 0.9/1000 accounting for 17% of people with epilepsy. For understanding what types of medical and other services might be required to care for epilepsy in the population, this information is quite valuable. This was the first and, to be noted, quite successful, effort to quantify the population burden of refractory epilepsy with a definition that included drug failure.