Drug-resistant epilepsy accounts for 1/4 of patients with epilepsy; it is defined as epilepsy that fails after application of two (or more) appropriate antiepileptic drugs in reasonable and adequate doses (either singly or in combination); frequent initial seizures and organic lesions, especially hippocampal sclerosis, are high-risk factors. Major mechanisms of drug resistance: P-glycoprotein and other efflux transporter expression are elevated in the brain of patients with drug-resistant epilepsy. Altered target of action of antiepileptic drugs: In the brains of patients with carbamazepine-resistant temporal lobe epilepsy, carbamazepine fails to block fast sodium currents in hippocampal dentate granule cells, presumably because polymorphisms in the SCN2A gene encoding the α2 subunit of the neuronal sodium channel make the organism resistant to drugs acting on sodium channels. Existing antiepileptic drugs control only the symptoms and rarely act on the pathogenesis. For example, autoantibodies to multiple ion channels and receptors associated with excitation and inhibition of neurons have been identified in the brains of some patients with epilepsy; general antiepileptic drugs usually do not work in these patients, and immunotherapy may be effective. Principles of treatment: Rule out pseudoresistance Identify extraepileptic symptoms Combination of drugs New drugs Surgery or minimally invasive Diet.