Drug-resistant epilepsy

Drug-resistant epilepsy (DRE), also known as refractory epilepsy, intractable epilepsy, or pharmacoresistant epilepsy, refers to a state in which an individual with a diagnosis of epilepsy is unresponsive to multiple first-line therapies. Based on the 2010 guidelines from the International League Against Epilepsy (ILAE), DRE is officially diagnosed following a lack of therapeutic relief in the form of continued seizure burden after trialing at least two antiepileptic drugs (AEDs) at the appropriate dosage and duration. The probability that the next medication will achieve seizure freedom drops with every failed AED. For example, after two failed AEDs, the probability that the third will achieve seizure freedom is around 4%. Drug-resistant epilepsy is commonly diagnosed after several years of uncontrolled seizures; however, in most cases, it is evident much earlier. Approximately 30% of people with epilepsy have a drug-resistant form. Achieving seizure control in DRE patients is critical, as uncontrolled seizures can lead to irreversible damage to the brain, cognitive impairment, and increased risk for sudden unexpected death in epilepsy. Indirect consequences of DRE include seizure-related injuries and accidents, impairment in daily life, adverse medication effects, increased co-morbidities (especially psychological), and increased economic burden.

Some clinical factors that are thought to be predictive of DRE include the female sex, focal epilepsy, developmental delay, status epilepticus, earlier age of onset of epilepsy, neurological deficits, having an abnormal EEG and/or imaging findings, genetic predisposition, association with the ABCB1 gene, and inborn errors of metabolism. Especially among pediatric populations, there is a growing association between DRE and genetic conditions or developmental disorders such as Lennox–Gastaut syndrome or Dravet syndrome.

There are numerous theories regarding the mechanisms of DRE, many of which have been studied in human and other animal models but the exact pathogenesis of the condition is still unclear.