Refractory Epilepsy

Unfortunately, 25–30% of people with epilepsy do not respond to adequate antiepileptic treatment and are said to suffer from “refractory epilepsy.” Although most people with refractory epilepsy have partial seizures, there is no definitive or all-inclusive definition of refractory epilepsy. Epilepsy can be considered medically intractable when satisfactory seizure control cannot be achieved with any of the potentially available effective antiepileptic drugs (AEDs), alone or in combination, at doses or levels not associated with unacceptable side effects (1). There is, however, no single step in the medical management of an adult or child with epilepsy after which he or she can be declared medically intractable.

Several important factors must be considered before a patient can be deemed intractable. One is the definition of “satisfactory” seizure control. Different people will define satisfactory in vastly different ways, depending on their professional and social circumstances. In some highly functional and potentially productive persons, even a few seizures per year can ruin their lives, careers, and aspirations. The type of seizure and the percentage that occur only at night will also influence a person's acceptance of a particular level of control. Unacceptable toxicity due to AEDs is also to some extent an individual matter; for example, the effect of sedation on the level of functioning in a professional environment. Overall, therefore, the refractory level must be assessed on an individual basis.

Typically, patients fail to respond to AEDs for reasons other than a lack of efficacy, as noted in Table 1(2). A proper seizure-type diagnosis is a crucial step in the successful management of epilepsy (“Diagnosis of Epilepsy,” pages 23–24). The choice of drug is determined by the type of epileptic syndrome (“Pharmacologic Treatment,” pages 33–34). Some AEDs are unsuitable for specific epilepsy types and syndromes. In addition, the possibility of pseudo-seizures has to be considered in any patient whose seizures are refractory.

Table 1.  Common causes and management of anticonvulsant therapy failure
Causes of failureDetectionManagement
NoncomplianceHistory; anticonvulsant level monitoringPatient instruction and education
Nonepileptic seizures or a combination of epileptic and nonepileptic seizuresHistory; video-EEG; suggestion; seizure markers (prolactin)Psychological counselling; psychotherapy
Incorrect seizure classification(History); video-EEGMedication adjustment
Incorrect choice or combination of drugs Medication adjustment
Inappropriate drug dosageAnticonvulsant level monitoringMedication adjustment

Another factor causing inadequate seizure control is poor patient compliance with prescribed AED treatment. Full understanding of the need to take the prescribed daily doses of AEDs and the necessary changes in lifestyle (e.g., to avoid seizures induced by sleep deprivation or alcohol) is critical for the success of therapy. At least 20% of patients with uncontrolled complex partial seizures may be expected to be noncompliant when they first present to an epilepsy clinic (3).


Children with intractable epilepsy usually have infantile spasms, myoclonic seizures, and/or complex partial seizures. Mental retardation and an early onset of seizures increase the likelihood of intractability (4). Partial epilepsy presenting in infancy and early childhood is often a serious disorder leading to neurologic deterioration and learning disabilities (5). In the absence of effective treatment, prognosis for mental and motor development is uniformly poor (6). Children are also at risk of side effects of prolonged AED administration and severe social and educational disability.


When seizures are considered intractable by the primary care physician or neurologist, evaluation and further medical treatment should be provided under the supervision of a neurologist in a specialist epilepsy centre. Such centres can offer comprehensive diagnostic and treatment services specifically designed for patients with intractable epilepsy, and alternative treatment modalities may be available such as inclusion in phase III trials with new AEDs (“Pharmacologic Treatment,” pages 33–34), epilepsy surgery (“Epilepsy Surgery,” pages 35–37), implantation of a vagus nerve stimulator (see later), or a ketogenic diet (see later).

Vagus nerve stimulation (VNS)

In a substantial number of people with epilepsy, the epileptogenic zone cannot be identified or is located in a functional brain area. Electrical stimulation of the vagus nerve is a recently available and effective palliative treatment for people with refractory epilepsy who are unsuitable candidates for curative resective surgery or who have experienced insufficient benefit from such a treatment.

The current consensus is that a third of people with refractory epilepsy have a considerable improvement in seizure control with a reduction in seizure frequency of ≥50%, another third experience a worthwhile reduction of seizure frequency between 30 and 50%, and in the remaining third of people, there is little or no effect (7). There is a tendency for efficacy to improve with longer duration of treatment—≤18 months postoperatively—but there is only limited information on patients becoming seizure free (8). VNS seems equally effective in children (9). Analysis of larger patient groups and insight into the mode of action may help to identify patients with epileptic seizures or syndromes that respond better to VNS.

Ketogenic diet

Ketogenic diets, in which the fat:(carbohydrate plus protein) ratio ranges from 2:1 to 5:1, have been shown to reduce seizure frequency in both children (10) and adults (11). In 40–50% of children, seizure frequency is more than halved after 1 year on the diet. This has been associated with a reduced need for AEDs with decreased risk and considerable cost savings (12). Although there is much less experience in adults, promising results have been obtained in both generalised and partial epilepsy.

The mechanism of action of ketogenic diets is unclear and, in children at least, there are nutritional concerns associated with its long-term use. Compliance can also be a problem although the diet is well tolerated when it is effective (13).


Refractory epilepsy is a significant problem. Recent advances in diagnostic techniques and increased treatment options have improved the situation, but further developments are needed.