Epilepsy


Table 1: Scheme for Categorising Outcome of a Therapeutic Intervention for Epilepsy


Outcome Category


1 A B C


2 A B C


3 A B C


Seizure-free*


Adverse effects: no Adverse effects: yes


Adverse effects: undetermined Treatment Failure**


Adverse effects: no Adverse effects: yes


Adverse effects: undetermined Undetermined***


Adverse effects: no Adverse effects: yes


Adverse effects: undetermined


1A 1B 1C


2A 2B 2C


3A 3B 3C


This table is level 1 of the International League Against Epilepsy (ILAE) framework for the definition of drug-resistant epilepsy, reproduced with permission from Elsevier. * Seizure freedom is defined as freedom from seizures for a minimum of three times the longest pre-intervention inter-seizure interval or 12 months, whichever is longer; ** Treatment failure is defined as recurrent seizure(s) after the intervention has been adequately applied; *** Undetermined is defined when the treatment has not been applied adequately for a valid assessment of the outcome or information is lacking to make the assessment.


Source: Kwan P, Brodie M, 2009.3


dose of at least 50% of the World Health Organization’s (WHO’s) defined daily dose (DDD).10


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.


Values of the Definition A Simple and Objective System


Previous studies have shown that response to the first AED is a powerful prognostic factor.11,12


Among patients with epilepsy who


failed to respond to two appropriate AEDs, whether as monotherapies or in combination, only 5–10% would achieve seizure control with a third drug.13–15


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.


forms the basis for level 2, which provides a core definition of drug-resistant epilepsy based on two or more ‘informative’ trials of AEDs resulting in a ‘treatment failure’ outcome.9


Seizure Freedom and Treatment Failure 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 pre-treatment interseizure interval is less than four months. In the case of persistent seizures, the outcome should be defined as treatment failure.9


It should be noted


that pre-treatment 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.


Undetermined Outcome and Informative Trial 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 categorised as undetermined. To determine treatment outcome, the AED should have been applied ‘adequately’. 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. 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 ‘adequate’ trial because this is influenced by a range of intrinsic and extrinsic factors. However, the definition does require a documented attempt to titrate the dose to a target, clinically-effective dose range. For standardisation in research settings, we empirically recommends that the AED should have been used for at least three months at a


58


Information to be Collected During Consultations Most patients with drug-resistant epilepsy have a long and complex treatment history. Due to insufficient information, treatments labelled 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 ‘drug-resistant epilepsy’ did not meet the ILAE definition because of a lack of basic information on AED history provided by the referring neurologists.17


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 categorisation 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–wake cycle and drug abuse.13


Early Pre-surgical Evaluation


Selected patients with drug-resistant epilepsy may benefit from non-pharmacological interventions, such as epilepsy surgery and vagus nerve stimulation.18


costly, and not without risk,19


Given that these interventions are invasive, 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.19–21


Diverse criteria used by different


groups might have contributed to the disparity in post-surgery outcome reported.22–25


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.


Promotion of a Global Outcome Database With a common language in categorising 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 centres around the world may be compared more directly or even combined for analysis. We believe that such a worldwide database will greatly


EUROPEAN NEUROLOGICAL REVIEW The DDD is the assumed average


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