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Drug-resistant epilepsy gets new definition.

BOSTON -- A new consensus definition of drug-resistant epilepsy promises to improve patient care and facilitate clinical research, according to the chair of a task force appointed by the International League Against Epilepsy Commission on Therapeutic Strategies.

According to the definition, epilepsy patients who have failed adequate trials of two tolerated, appropriately chosen and used antiepileptic drug regimens, whether as single or combination therapies, should be considered drug-resistant and referred for specialty evaluation.

The identification of drug-resistant, or refractory epilepsy substantially influences clinical decision making as well as treatment research and development. Appropriately labeling a patient as drug resistant, for example, might lead to more timely consideration of surgical or other nonpharmacologic treatment, such, as vagal nerve stimulation, he said. In addition, recognizing drug resistance in patients may provide insight into the neurobiology of the disease, which in turn can inform the development of new treatment, Dr. Patrick Kwan said at the annual meeting of the American Epilepsy Society.

The lack of a precise definition for refractory epilepsy until this time has meant the reliance on diverse criteria by clinicians and researchers, "which makes it difficult to compare findings across studies and to develop evidence-based practice recommendations," said Dr. Kwan of the Chinese University of Hong Kong, Prince of Wales Hospital.

In an effort to level the playing field, the new definition is built on a framework that comprises a general scheme for categorizing patients' responses to each therapy and determining trial adequacy, he said.

For example, if a patient stops taking a given drug, it's important to know the circumstances of the withdrawal, according to Dr. Jacqueline French, professor of neurology at New York University and cochair of the therapeutic strategies commission.

"Was the drug ineffective after being titrated to its clinically effective dose range or was it withdrawn because of an adverse effect?" The former scenario will have some bearing on the presumed efficacy of other antiepileptic drugs, she stressed in a press briefing. The latter scenario, on the other hand, does not indicate a clinical failure of the drug with respect to its efficacy for seizure control, and as such should not be placed under the "drug-resistant" umbrella, she said.

The definition also requires that therapeutic interventions be appropriate for patients' epilepsy and seizure type and have been proven effective previously preferably in randomized, controlled studies, Dr. French said.

With respect to trial adequacy, the task force deemed the following information necessary for assessing whether a drug intervention study is appropriate and informative for evaluating efficacy:

*The nature of the intervention, such as the type of drug.

* The mode of application, including the formulation, dose, dosing interval, and patient compliance.

* The duration of exposure.

* The occurrence of seizures and adverse effects during the trial period.

* The nature of the intervention, such as the type of drug.

* Whether there was an effort to optimize dose.

* The reasons for drug discontinuation, if applicable.

The outcomes of trials that do not fulfill these criteria should be considered "undetermined," and as such should not be included in the drug failure count, Dr. Kwan stressed. Practically, this means that some patients may "fail," in some manner, multiple antiepileptic drugs before they fail two appropriate, informative trials, he said.

Following two adequate, therapeutic trials, patients who do not achieve seizure freedom, defined by the task force as being seizure free for at least 1 year or three times the longest inter-seizure interval, should be referred from primary care or general neurology care to specialist centers for further evaluation, Dr. Kwan said.

Although it is expected that the definition will be adopted by clinicians at all health care levels, primary care physicians in particular will have a major role in applying the definition, as they are the most likely to have long-term relationships with these patients, he said.

Importantly, "by applying the definition, practitioners [and patients] can be alerted to the type of information that should be collected during clinical consultation," Dr. Kwan and his task force colleagues wrote online in Epilepsia. "The proposed definition also has implications for the design of randomized drug trials and should prove useful in the selection of patients for such trials in which the criteria for considering a patient drug resistant are often poorly described," they wrote, noting that a "standard definition of drug resistance can help ensure comparable results across trials" (Epilepsia 2009 Nov. 3 [doi: 10. 1111/j 1528-11672009.02397.x]).

The definition is intended to be applicable to all patients, regardless of age of onset, type of epilepsy, seizure frequency, or seizure etiology, according to task force member Dr. Alexis Arzimanoglou of University Hospitals of Lyon (France). "The early detection of [drug-resistant] epilepsy should lead to early referral to a specialty center for evaluation and treatment," he said. The definition "offers a new path for the early identification of those patients who may be cured from their epilepsy."

Dr. Kwan stressed that the proposed definition is not the last word on drug-resistant epilepsy but rather it represents "a testable hypothesis and a common starting point. Revision may be needed as more high-quality data become available."

Disclosures: Members of the task force, whose work was funded by the ILAE, disclosed no relevant financial conflicts.
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Title Annotation:NEUROLOGY
Author:Mahoney, Diana
Publication:Internal Medicine News
Geographic Code:1USA
Date:Feb 1, 2010
Words:867
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