{"id":806,"date":"2011-06-04T10:11:07","date_gmt":"2011-06-04T10:11:07","guid":{"rendered":"https:\/\/touchneurology.com\/2011\/06\/04\/update-and-overview-of-the-international-league-against-epilepsy-consensus-definition-of-drug-resistant-epilepsy-2\/"},"modified":"2011-06-04T10:11:07","modified_gmt":"2011-06-04T10:11:07","slug":"update-and-overview-of-the-international-league-against-epilepsy-consensus-definition-of-drug-resistant-epilepsy-2","status":"publish","type":"post","link":"https:\/\/touchneurology.com\/epilepsy\/journal-articles\/update-and-overview-of-the-international-league-against-epilepsy-consensus-definition-of-drug-resistant-epilepsy-2\/","title":{"rendered":"Update and Overview of the International League Against Epilepsy Consensus Definition of Drug-resistant Epilepsy"},"content":{"rendered":"

Approximately 50 million people have epilepsy worldwide,1<\/sup> up to one-third of whom continue to experience seizures despite drug treatment.2<\/sup> Diverse criteria have been used to define drug resistance by different researchers, making it difficult or even impossible to compare the results across different studies. To improve patients\u2019 care and facilitate clinical research, the International League Against Epilepsy (ILAE) recently proposed a consensus definition of drug-resistant epilepsy. Given that most patients are initially managed by general physicians or general neurologists, it is hoped that the definition framework will provide clear and simple guidance in identifying patients with pharmacoresistance for early referral to specialist centers for evaluation.3<\/sup> This article outlines the framework of the consensus definition, explains how to apply it in practice and discusses the future development of its use.<\/p>\n

The Burden of Drug-resistant Epilepsy<\/strong>
Recurrent seizures are associated with a range of deleterious consequences. Seizure-related deaths may account for up to 40% of all deaths in patients with chronic epilepsy. The rate of sudden unexpected death, which accounts for 7\u201317% of deaths among epilepsy patients, is estimated to be up to 27-fold higher in those with ongoing seizures compared to those who are seizure free.4,5<\/sup><\/p>\n

Uncontrolled seizures restrict patients\u2019 social activities, reducing their ability to hold a driving license or keep a job. Refractory epilepsy places substantial stress on the patient\u2019s family members and caregivers. It is also a great economic burden for society, through expenditures in healthcare and unemployment. In a study of the cost of epilepsy in the US, it was reported that the average montly cost per individual in the patient-based analysis was $1,490, whereas the average annual cost per individual in the population-based analysis was $1,510 with average yearly costs between $1,480 and $1,740.6<\/sup> In patients whose epilepsy failed to respond to several antiepileptic drugs (AEDs), the chance of significant benefit from a further AED change is estimated to be <5% per year.7<\/sup> For these patients, resective surgery is a potential therapeutic option.8<\/sup> Early diagnosis of drug resistance using a universally-accepted definition can facilitate the selection of patients for such non-drug therapies and potentially alleviate the medicosocial and economic burden of refractory epilepsy.The International League Against Epilepsy
Consensus Definition
Definition Framework<\/strong>
The proposal defines drug-resistant epilepsy as failure of adequate trials of two (or more) tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. The overall framework of the definition comprises two \u2018hierarchical\u2019 levels. Level 1 provides a general template or scheme to categorize the outcome to each therapeutic intervention (whether pharmacological or non-pharmacological). To categorize the outcome accurately, a minimum dataset of details of the AED history, including the dose and duration the drug was used for, must be available. This is the most important factor in determining whether the trial of an intervention is \u2018informative\u2019 in an individual patient. The categories of outcome include \u2018seizure-free\u2019, \u2018treatment failure\u2019, and \u2018undetermined\u2019. These are further subdivided according to whether the patient experienced adverse effects (see Table 1). Level 1 forms the basis for level 2, which provides a core definition of drug-resistant epilepsy based on two or more \u2018informative\u2019 trials of AEDs resulting in a \u2018treatment failure\u2019 outcome.9<\/p>\n

Seizure Freedom and Treatment Failure<\/strong>
Seizure freedom is defined as freedom from all seizures, including auras, for at least three times the longest pre-treatment interseizure interval or 12 months if the longest pretreatment interseizure interval is less than four months. In the case of persistent seizures, the outcome should be defined as treatment failure.9<\/sup> It should be noted that pretreatment interseizure interval should be defined for each intervention separately. It follows that if the seizures are very infrequent, the patient may need to be followed up for many years to determine outcome. In this case, the longest pre-intervention interseizure interval should be determined from seizures occurring within the preceding 12 months.<\/p>\n

Undetermined Outcome and Informative Trial<\/strong>
Level 1 outcome should be recorded as undetermined if the minimum dataset is unavailable. The minimum dataset contains the details of the intervention history, such as the duration of treatment, the dosage of AEDs and reason for withdrawal (if applicable). In the absence of such information, it cannot be confidently determined whether the epilepsy was truly under control or unresponsive to treatment. In this situation, the outcome to the intervention should be categorized as undetermined. To determine treatment outcome, the AED should have been applied \u2018adequately\u2019. This may not be the case in some circumstances, for example when an AED is withdrawn due to an allergic rash or is stopped early due to poor tolerability at low dosage.<\/p>\n

In these situations, the outcome should be considered undetermined. The proposed definition does not specify the dose or duration of each drug that constitutes an \u2018adequate\u2019 trial because this is influenced by a range of intrinsic and extrinsic factors. The definition does, however, require a documented attempt to titrate the dose to a target, clinically-effective dose range. For standardization in research settings, we empirically recommends that the AED should have been used for at least three months at a dose of at least 50% of the World Health Organization\u2019s (WHO\u2019s) defined daily dose (DDD).10<\/sup> The DDD is the assumed average maintenance amount for each drug in adults. Obviously, because some patients respond to low doses there is no dosage requirement in defining freedom from seizures.<\/p>\n

Values of the Definition
A Simple and Objective System<\/strong>
Previous studies have shown that response to the first AED is a powerful prognostic factor.11,12<\/sup> Among patients with epilepsy who failed to respond to two appropriate AEDs, whether as monotherapies or in combination, only 5\u201310% would achieve seizure control with a third drug.13\u201315<\/sup> This rate declines further in subsequent trials.16 These observations highlight the prognostic importance of early response to AED treatment. Given that most epilepsy patients are initially managed by non-specialists, the consensus definition is deliberately designed to be a simple and objective system for use by clinicians at all healthcare levels.Information to be Collected During Consultations<\/strong>
Most patients with drug-resistant epilepsy have a long and complex treatment history. Due to insufficient information, treatments labeled as failures might not have truly failed because they have not been tried adequately due to, for instance, allergic reaction at low dose or early withdrawal for reasons unrelated to treatment. Reported in an abstract, Aparicio and colleagues noted that 27 of 30 patients referred for evaluation of \u2018drug-resistant epilepsy\u2019 did not meet the ILAE definition because of a lack of basic information on AED history provided by the referring neurologists.17<\/sup> Thus, the definition may help clinicians and patients to be alerted to the essential information that needs to be collected during routine consultations when initiating a new AED for categorization of its outcome in the future. Patients should also be educated on the avoidance of triggers of seizure relapse, particularly non-compliance and lifestyle factors, such as sleep deprivation, excessive alcohol intake, an irregular sleep\u2013wake cycle, and drug abuse.13<\/sup><\/p>\n

Early Presurgical Evaluation<\/strong>
Selected patients with drug-resistant epilepsy may benefit from non-pharmacological interventions, such as epilepsy surgery and vagus nerve stimulation.18<\/sup> Given that these interventions are invasive, costly, and not without risk,19<\/sup> confirming the diagnosis of drug resistance is generally considered a prerequisite. There is no consensus definition of drug resistance for the purpose of selecting patients for epilepsy surgery.19\u201321<\/sup> Diverse criteria used by different groups might have contributed to the disparity in postsurgery outcome reported.22\u201325<\/sup> By providing the minimum core criteria, the proposed ILAE definition represents a common platform that can be adapted specifically for the purpose of selecting patients for non-drug therapies. This will avoid delay in evaluating patients for these therapeutic options and facilitate meaningful comparison of effectiveness reported in different studies.<\/p>\n

Promotion of a Global Outcome Database<\/strong>
With a common language in categorizing and defining treatment response, it becomes possible to establish a global database of epilepsy outcomes. Through adopting the same criteria to record information on drug response, research findings from different centers around the world may be compared more directly or even combined for analysis. We believe that such a worldwide database will greatly improve our understanding of the long-term prognosis of epilepsy so that more rational treatment strategies may be formulated.<\/p>\n

Future Work<\/strong>
The proposed definition should not be considered as a fait accompli but a work in progress that should be tested in rigorous prospective studies. Its limitations and areas that need to be refined as new evidence emerges will now be discussed.<\/p>\n

Defining an \u2018Adequate\u2019 Drug Trial<\/strong>
There are multiple internal and external factors that influence the dose required for an \u2018adequate\u2019 trial of an AED, such as:9<\/p>\n