Refractory Epilepsy

By: Annemarie Dechellis

What is Refractory Epilepsy?

Refractory epilepsy is a type of epilepsy that is characterized by resistance to seizure medications (i.e. AEDs). Refractory epilepsy may also be referred to as drug resistant, treatment non-responder, intractable, or pharmacoresistant epilepsy,  (Engel, 2014; French, 2016). For some time there was not a clear definition of what classified as refractory epilepsy. However, the commonly used definition today, proposed by the International League Against Epilepsy (ILAE), suggests that refractory epilepsy occurs when a person has not become, or remained, seizure free after trials of two different seizure medications (Fisher, Shafer, & Sirven, 2013; Strezlczyk et al., 2017). About one third (33%) of people with epilepsy develop refractory seizures at some point in their life. The most common forms of refractory epilepsy are generalized or focal seizures (Johns Hopkins, n.d.). 


Currently, it is not fully understood why some people develop refractory epilepsy and others do not. An incorrect diagnosis or treatment plan may cause someone’s condition to appear drug-resistant. Lifestyle factors, such as sleep quality and stress, can increase the likelihood of seizures even when taking seizure medication. However, it may be the case that a proper diagnosis was made and seizures are resistant to medication (Engel, 2014; Risher, Shafer, & Sirven, 2013).  



If changes in medication do not provide freedom from seizures, surgery is typically sought as the next treatment option. Growing research has shown that surgery can be a successful treatment option for refractory epilepsy— with about an 80% success rate and a low occurrence of complications at about 5% (Engel, 2014; Mashhad et al., 2020). In a 2017 study, 57 children under the age of 18 underwent surgery for drug-resistant epilepsy, and one year later 77% of patients were not only seizure free but also reported cognition, behavior, and quality of life had improved (Dwivedi et al., 2017). The benefits of surgery for refractory epilepsy can include potentially permanent freedom from seizures, reduced toxicity from medication, and positive behavioral and cognitive changes. However, the downside to surgery is the cost, surgical and anesthesia risk, and treatment with medication may still be necessary (Engel, 2014; Granata et al., 2009). 

Surgery is not an option for all forms of refractory epilepsy. Types of epilepsy that can be traced to a specific region or structure of the brain are more likely to qualify for surgical treatment than epilepsy that is generalized in the brain. For example, surgical treatment can be an option for Gelastic seizures caused by a hypothalamic haramtoma (i.e., a benign tumor on the hypothalamus) because it is localized in the brain (Engel, 2014; Dwivedi et al., 2017). For non-operable refractory epilepsy alternative ways to treat and manage seizure activity include neuromodulation, special diet, and lifestyle changes.


Neuromodulation therapy is the use of electrical stimulation to alter, excite, or inhibit neural activity, and is typically administered with an implantation device (Eastin & Lopez-Gonzalez, 2017; Sakas et al., 2007). Types of invasive neuromodulation therapy include deep brain stimulation, responsive neurostimulation, and vagus nerve stimulation. There are also non-invasive approaches such as transcranial magnetic stimulation (Foit, Bernasconi, & Ladbon-Bernasconi, 2020). Vagus Nerve Stimulation (VNS) is the most commonly cited form of neuromodulation therapy for refractory epilepsy. VNS is an invasive therapy in which a device is implanted under the skin that connects to the vagus nerve on the left side of the neck. While results are not immediate, about 25 to 30% of people may experience up to a 50% decrease in seizure activity after a few months of treatment (Sirven & Shafer, 2014). In one case, a 16-year-old boy with drug resistant epilepsy was having four to five seizures a day. After treatment with VNS, he experienced only one to two seizures a month (Chandra et al., 2020). Similar to surgical treatment, patients who received neuromodulation therapy may also experience positive cognitive, behavioral, and mood changes (Foit et al., 2020).


The Ketogenic or Keto Diet, which is a high fat and low carbohydrate diet, is another treatment option to help reduce seizures (Engel, 2014; Granata et al., 2009; Johns Hopkins, n.d.). Evidence suggests the Keto Diet can help children achieve seizure freedom or seizure reduction and can have a positive impact on mood and behavior such as reduced anxiety and increased productivity. Similar results, however, have not been well documented in adults, and the Keto Diet can be difficult to maintain (Granata et al., 2009; Ijff et al., 2016; Martin-McGill et al., 2020). It’s important to note that modified, easier to maintain versions of the Keto Diet, the Atkins diet, and Low Glycemic Index diets may reduce seizure frequency, and have a positive effect on mood, cognition, and behavior (Martin-McGill et al., 2020; Sirven & Shafer, 2014).

Impact on Everyday Life

Living with drug resistant epilepsy can have a significant impact on one’s quality of life. People may live in an anxious state of anticipation, worrying about when their next seizure may occur, which can interfere with work, school, and social activities (Johns Hopkins, n.d.). Depression, anxiety, and cognitive decline occur at a higher rate for people with refractory epilepsy compared to the general population (El-Senousey et al., 2012; Johns Hopkins, n.d.; Strezlczyk et al., 2017). Moreover, there is the financial burden of living with drug-resistant epilepsy. Trying multiple medications alone is expensive, and newly developed drug treatments tend to be even more costly (Granata et al., 2013). A German study found that the annual costs of medication for people with severely drug resistant epilepsy were between €4,565 and €5,294 (Strezlcyk et al., 2017).    


The complexity of creating a successful treatment plan for refractory epilepsy highlights the need for multifaceted, holistic treatments to achieve both seizure freedom and improve quality of life (Granata et al., 2009). With about one third of people with epilepsy experiencing drug-resistant seizures, it is critical not only to continue research for the development of new treatment options, but to ensure alternative treatments are accessible and affordable. Educating others to combat the stigma associated with epilepsy can help alleviate feelings of anxiety and stress people living with epilepsy experience. Lifestyle changes such as diet, reducing stress, and improving sleep quality can aid seizure management. 

References :

Chandra, P. S., Samala, R., Agrawal, M., Doddamani, R. S., Ramanujam, B., & Tripathi, M. (2020). Vagal nerve stimulation for drug refractory epilepsy. Neurology India, 68, S325–S327.

Dwivedi, R., Ramanujam, B., Chandra, S., Sapra, S., Gulati, S., Kalaivani, M., Gang, A., Bal. C. S., Tripathi, M., Dwivedi, S.N., Sagar, R., Sarkar, C., et al. (2017). Surgery for drug-resistant epilepsy in children. The New England Journal of Medicine. 1639-1647.

Eastin, T.M., & Lopez-Gonzalez, M.A. (2017). Stimulation and neuromodulation in the treatment of epilepsy. Brain Sciences, 8(1), 1-10.  

El-Senousey, M.Y A., Aboelsafa, A.A., El-Gammal, T.M., Ghali, A.A., El-Heneedy, Y.A., & Mohamed, R.E. (2012). Cognitive decline in patients with refractory complex partial seizures. Egyptian Journal of Neurology, Psychiatry & Neurosurgery, 49(2), 149–156.

Engel, J.Jr. (2014). Approaches to refractory epilepsy. Annals of Indian Academy of Neurology, 17(Suppl 1), S12- S17.

Fisher, R., Shafer, P.O., & Sirven, J.I. (2013). Refractory seizures. Epilepsy Foundation.

Foit, N. A., Bernasconi, A., & Ladbon-Bernasconi, N. (2020). Contributions of imaging to  neuromodulatory treatment of drug-refractory epilepsy. Brain Sciences, 10(10), 1-14

French, J.A. (2006). Refractory epilepsy: one size does not fit all. Epilepsy currents, 6(6), 177-180.

Granata, T., Marchi, N., Carlton, E., Ghost, C., Gonzalez-Martinez, J., Alexopoulos, A. V., & Janigro, D. (2009). Management of the patient with medically refractory epilepsy. Expert review of neurotherapeutics, 9(12), 1791-1802. 

Ijff, D. M., Postulart, D., Lambrechts, D., Majoie, M., de Kinderen, R., Hendriksen, J., Evers, S., & Aldenkamp, A. P. (2016). Cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: A randomized controlled trial. Epilepsy & Behavior, 60, 153-157. 

Refractory epilepsy. (n.d.). Johns Hopkins Medicine. Retrieved February 19, 2021, from

Mashhad, J.M., Harati, H., Parooie, F., & Salarzaei, M. (2020). Epilepsy surgery for refractory seizures: a systematic review and meta-analysis in different complications. Egyptian Journal of Neurology, Psychiatry & Neurosurgery, 56(1), 1–12.

Martin-McGill, K.J., Bresnahan, R., Levy, R.G., & Cooper, P.N. (2020). Ketogenic diets for drug‐resistant epilepsy. Cochrane Database of Systematic Reviews, 6, 1-3.

Sakas, D.E., Panaourias, E.G., Simpson, B.A., & Krames, E.S. (2007). An introduction to operative neuromodulation and functional neuroprosthetics, the frontiers of clinical neuroscience and biotechnology. In Sakas, D.E., Simpson, B.A., & Krames, E.S. (Eds.), Operative Neuromodulation: Function Neuroprosthetic Surgery. An Introduction. (Vol. 1, pp. 3-10). SpringerWienNewYork.

Sirven, J.I., & Shafer, P.O. (2014). Treating refractory epilepsy. Epilepsy Foundation.

Strezlczyk, A., Griebel, C., Lux, W., Rosenow, F., & Reese, J. (2017). The burden of severely drug-refractory epilepsy: A comparative longitudinal evaluation of mortality, morbidity, resource use, and cost using German health insurance data. Frontier in Neurology, 8(22), 712.

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