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Pharmacoresistance in Epilepsy

How Should It Be Defined?

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Abstract

Although terms such as ‘treatment-resistant’, ‘pharmacoresistant’ and ‘refractory’ epilepsy are ubiquitous in the epileptological literature, only seldom has an attempt been made to define them clearly. To label these terms as intuitive is simply avoiding the problem, and ignores the fact that ‘intuitions’ can vary widely. In fact, when definitions have been proposed, they have been as disparate and numerous as the scientists using them. For example, there is no agreement on how many drugs should be tried before a patient can be considered as having ‘pharmacoresistant’ epilepsy, and there is uncertainty as to whether a definition should include specific requirements about dosages, minimum seizure frequency and minimum duration of the disease.

While it is acknowledged that definitions may vary depending on the issue being addressed, proliferation of too many definitions or, even worse, avoidance of definitions altogether may hamper the interpretation and comparability of studies assessing the effects of anticonvulsants. The problem is especially acute when selecting patients with pharmacoresistant epilepsy for trials of new anticonvulsants: heterogeneity in the characteristics of these patients due to a loose definition of pharmacoresistance is the main explanation for the wide differences in outcome between studies using the same drug and comparable designs.

The selection of patients for such studies could be improved greatly by introducing a graded system of drug resistance. According to a recent proposal, grade I resistance may include epilepsy that is unresponsive to a maximally tolerated dosage of 1 primary drug; grade II may include epilepsy that is unresponsive to 2 primary drugs used sequentially (IIA) or in combination (IIB); and grade III may include epilepsy that is unresponsive to 3 or more primary drugs used sequentially (IIIA) or in combination (IIIB).

The main advantage of these categories is that they allow for a prediction of the probability of response to a subsequently added drug. A case can also be made for differentiating true pharmacoresistance from pseudoresistance, a condition defined as the persistence of seizures because of poor compliance, inappropriate treatment, inappropriate assessment of response, or inadequate dosage or administration regimen.

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  1. Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Piazza Botta 10, 27100, Pavia, Italy

    Emilio Perucca

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Perucca, E. Pharmacoresistance in Epilepsy. Mol Diag Ther 10, 171–179 (1998). https://doi.org/10.2165/00023210-199810030-00002

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