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/or accidents, impairment in daily life, adverse medication effects, increased co-morbidities (especially psychological), and increased economic burden, etc.

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 mechanism of action behind DRE, many of which have been studied in human and/or animal models. However, the exact pathogenesis of this condition still remains unclear.

The first step is for physicians to refer their DRE patients to an epilepsy specialist in a comprehensive epilepsy center where further diagnostic work-up can be performed.

One of the first steps in management of drug-resistant epilepsy is confirming the diagnosis by EEG. Typically patients are admitted to hospital for prolonged EEG monitoring with video technology used to capture clinical events as they occur. Typically patients are taken off their anti-seizure medications in order to characterize the evolution of seizure symptoms and their relation with changes in electrical activity of brain. This is done while simultaneously minimizing the adverse consequences of seizures. Additional maneuvers to provoke seizures are also frequently performed, like sleep deprivation, photic stimulation, and hyperventilation. This study can take anywhere from 1–14 days. The length of the study depends on factors like baseline seizure frequency, the number and type of seizure medications the patient is taking prior to the study, institutional protocols, etc. The goal is to record 3-4 typical seizures, though in some cases more or fewer seizures may need to be recorded. After this evaluation, some patients may be determined to have non-epileptic causes of their symptoms, e.g., syncope, psychogenic nonepileptic seizures, cardiac arrhythmia, etc.

For patients who are confirmed to have epilepsy, this testing helps further elucidate the type of epilepsy (generalized vs focal), type of seizures (atonic, absence, GTC, etc.), and can be used for pre-surgical evaluation or to guide further management. Changes on EEG in relation to clinical seizure symptoms are used to determine the likely area of the brain responsible (symptomatic zone) and by extrapolation the area where seizure activity likely starts (seizure onset zone). In some specific cases, prolonged EEG may be done as an outpatient or ambulatory study where the patient goes home with an EEG set-up. This type of monitoring is usually limited to 2–3 days and patients are not taken off their AEDs.

MRI of brain is the most common first-line neuroimaging modality to be used in evaluation of a structural cause of epilepsy. A 3 Tesla MRI is generally recommended, as opposed to scanning on lower magnet strengths. MRI for evaluation of epilepsy often include T1 and T2 images that are optimized to appreciate gray-white matter differentiation and oblique coronal images along the axis of hippocampus. Identification of common lesions associated with epilepsy, like focal cortical dysplasia, mesial temporal sclerosis, microencephalocele, and heterotopia, require thorough review of images by trained clinicians, as the changes can be very subtle and easily missed if not specifically evaluated for. Oftentimes, repeat MRI is required to elucidate an etiology to epilepsy, and typically an epilepsy imaging protocol is followed to identify these subtle changes. There is ongoing quantitative analysis of standard MRI images to identify subtle lesions and use of stronger magnetic fields, like 7 Tesla MRI, for better delineation of anatomical details. Additionally, not all structural abnormalities seen on MRI correlate with epilepsy and may represent incidental findings.

Positron emission tomography scan (PET) using the ¹⁸F-FDG radiotracer can also be used in evaluation of DRE. Its use in epilepsy evaluation is based on the premise that areas of the brain responsible for seizure onset also have persistent metabolic dysfunction and do not use glucose at the same rate as other areas of the brain. Specifically, during seizure activity (ictal) one would expect a hypermetabolic state with increased radiotracer uptake on PET scan, while in between events (interictal) one would expect a hypometabolic state with lower radiotracer uptake on PET scan. Oftentimes findings on PET scan are often correlated with other diagnostic workup that has already/concurrently been obtained to further localize an epileptogenic area of the brain, particularly in the case of focal epilepsy. Other ligands like ¹¹C-flumazenil, 1¹C-alpha-methyl-L-tryptophan, ¹¹C-methionine, have also been used, mostly on research basis to help identify areas of seizure onset.