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Article
The Intrinsic Severity Hypothesis of Pharmacoresistance to Antiepileptic Drugs
Epilepsia (2013)
  • Michael A. Rogawski, University of California - Davis
Abstract
Pharmacoresistance to antiepileptic drugs (AEDs) is a barrier to seizure freedom for many persons with epilepsy. For nearly two decades, pharmacoresistance has been framed in terms of factors affecting the access of AEDs to their molecular targets in the brain or the actions of the drugs on these targets. Shortcomings in this prevailing view led to the formulation of the intrinsic severity hypothesis of pharmacoresistance to AEDs, which is based on the recognition that there are neurobiologic factors that confer phenotypic variation among individuals with etiologically similar forms of epilepsy and postulates that more severe epilepsy is more difficult to treat with AEDs. In recent years, progress has been made identifying potential genetic mechanisms of variation in epilepsy severity, including subclinical mutations in ion channels that increase or reduce epilepsy severity in mice. Efforts are underway to identify clinically important genetic modifiers. If it can be demonstrated that such severity factors play a role in pharmacoresistance, treatments could be devised to reverse severity mechanisms. By overcoming pharmacoresistance, this new approach to epilepsy therapy may allow drug refractory patients to achieve seizure freedom without side effects.
Keywords
  • seizure,
  • genetic modifier,
  • refractory epilepsy,
  • multidrug resistance transporter,
  • voltage-activated sodium channel
Publication Date
2013
Publisher Statement
Available at: http://dx.doi.org/10.1111/epi.12182
Citation Information
Michael A. Rogawski. "The Intrinsic Severity Hypothesis of Pharmacoresistance to Antiepileptic Drugs" Epilepsia Vol. 54 Iss. Suppl. 2 (2013)
Available at: http://works.bepress.com/michael_rogawski/53/