management of drug-resistant epilepsy

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management of drug-resistant epilepsy
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Drug-resistant epilepsy (DRE), also known as refractory epilepsy or pharmacoresistant epilepsy, is defined as failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drugs (AED schedules) (whether as monotherapies or in combination) to achieve sustained seizure freedom.JOURNAL, Kwan, Patrick, Arzimanoglou, Alexis, Berg, Anne T., Brodie, Martin J., Allen Hauser, W., Mathern, Gary, Moshé, Solomon L., Perucca, Emilio, Wiebe, Samuel, 2010-06-01, Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies, Epilepsia, en, 51, 6, 1069–1077, 10.1111/j.1528-1167.2009.02397.x, 1528-1167, 19889013, 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%.JOURNAL, Kwan, Patrick, Brodie, Martin J., 2000-02-03, Early Identification of Refractory Epilepsy, New England Journal of Medicine, 342, 5, 314–319, 10.1056/NEJM200002033420503, 0028-4793, 10660394, 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.JOURNAL, Brodie, Martin J., 2013-05-01, Road to refractory epilepsy: The Glasgow story, Epilepsia, en, 54, 5–8, 10.1111/epi.12175, 1528-1167, 23646962, When 2 AEDs regimens have failed to produce sustained seizure-freedom, it is important to initiate other treatments to control seizures. Next to indirect consequences like injuries from falls, accidents, drowning and impairment in daily life, seizure control is critical because uncontrolled seizures -specifically generalized tonic clonic seizures- can damage the brain and increase the risk for sudden unexpected death in epilepsy called SUDEP.JOURNAL, Hesdorffer, Dale C., Tomson, Torbjorn, Benn, Emma, Sander, Josemir W., Nilsson, Lena, Langan, Yvonne, Walczak, Thaddeus S., Beghi, Ettore, Brodie, Martin J., 2011-06-01, Combined analysis of risk factors for SUDEP, Epilepsia, en, 52, 6, 1150–1159, 10.1111/j.1528-1167.2010.02952.x, 21671925, 1528-1167, JOURNAL, Langan, Y., Nashef, L., Sander, J. W., 2005-04-12, Case-control study of SUDEP, Neurology, en, 64, 7, 1131–1133, 10.1212/01.WNL.0000156352.61328.CB, 0028-3878, 15824334, The first step is for physicians to refer their DRE patients to an epilepsy center in which a presurgical evaluation can be carried out in order to assess whether a patient is a candidate for epilepsy surgery or not. For those patients who are not surgical candidates, those who decline brain surgery or those in which brain surgery fails to produce long term seizure freedom, vagus nerve stimulation and/or a diet can be recommended.


In epilepsy surgery a distinction can be made between resective and disconnective procedures. In a resective procedure the area of the brain that causes the seizures is removed. In a disconnective procedure the neural connections in the brain that allow the seizures to spread are disconnected. In most cases epilepsy surgery is only an option when the area of the brain that causes the seizures - the so-called epileptic focus can be clearly identified and is not responsible for critical functions such as language. Several imaging techniques such as magnetic resonance tomography and functional techniques like electrocorticography are used to demarcate the epileptic focus clearly.

Lobe resection

Temporal lobe epilepsy (TLE) in which the epileptic focus is in the temporal lobe, is one of the most common types of epilepsy in adolescents and adults. Hence temporal lobe resection, during which the whole temporal lobe or just a part of the temporal lobe for example the hippocampus or the amygdala is removed, is the most common epilepsy surgery procedure. Between 40 and 60% of patients that undergo temporal lobe resection are continuously seizure freeJOURNAL, Marks, William J., 2003-09-01, Long-term Outcomes of Temporal Lobe Epilepsy Surgery, Epilepsy Currents, 3, 5, 178–180, 10.1046/j.1535-7597.2003.03509.x, 1535-7597, 557956, 15902315, JOURNAL, Jutila, L., Immonen, A., Mervaala, E., Partanen, J., Partanen, K., Puranen, M., Kälviäinen, R., Alafuzoff, I., Hurskainen, H., 2002-11-01, Long term outcome of temporal lobe epilepsy surgery: analyses of 140 consecutive patients,weblink Journal of Neurology, Neurosurgery & Psychiatry, en, 73, 5, 486–494, 10.1136/jnnp.73.5.486, 1468-330X, 1738104, 12397139, The surgery itself is very safe with a mortality of 0%JOURNAL, McClelland S, III, Guo H, Okuyemi KS, 2011-06-13, POpulation-based analysis of morbidity and mortality following surgery for intractable temporal lobe epilepsy in the united states, Archives of Neurology, 68, 6, 725–729, 10.1001/archneurol.2011.7, 0003-9942, 21320984, JOURNAL, Fisch, Bruce, 2011-11-01, Anterior Temporal Lobectomy – How Safe Is It?, Epilepsy Currents, 11, 6, 186–188, 10.5698/1535-7511-11.6.186, 1535-7597, 3220424, 22129637, (:File:///C:/Users/mdibue-adjei/Box Sync/Maxine/Projekte/Dare-to-Ask Website/Dare to ask Website Text ENG.docx#ftn3|.) The risk for neurologic complications from a temporal lobe resection is around 3 to 7%JOURNAL, Salanova, V., Markand, O., Worth, R., 2002-02-01, Temporal Lobe Epilepsy Surgery: Outcome, Complications, and Late Mortality Rate in 215 Patients, Epilepsia, en, 43, 2, 170–174, 10.1046/j.1528-1157.2002.33800.x, 1528-1167, JOURNAL, Fisch, Bruce, 2011-11-01, Anterior Temporal Lobectomy – How Safe Is It?, Epilepsy Currents, 11, 6, 186–188, 10.5698/1535-7511-11.6.186, 1535-7597, 3220424, 22129637,


if the source of seizures is a lesion for example a scar tissue from a brain injury a tumor or malformed blood vessels this lesion can be removed surgically in a lesionectomy.

Corpus callosotomy

Corpus callosotomy is a palliative procedure for specially severe cases of epilepsy. This corpus callosum is a large bundle of nerve fibers that connects both brain halves with each other. To prevent the spreading of seizures from one brain hemisphere (brain half) to the other the corpus callosum can be split. This procedure is mostly carried out on patients with so-called drop attacks that come with a very high risk of injury and in which the epileptic focus is not clearly delimitable. It is very rare that a corpus callosotomy causes seizure freedom however in half of the patients the dangerous drop attacks are less severe.JOURNAL, Maehara, Taketoshi, Shimizu, Hiroyuki, 2001-01-23, Surgical Outcome of Corpus Callosotomy in Patients with Drop Attacks, Epilepsia, en, 42, 1, 67–71, 10.1046/j.1528-1157.2001.081422.x, 1528-1167, After a corpus callosotomy among others there is the risk that language is temporarily or permanently impaired. The younger a patient is at the time of the corpus callosotomy, the better the prognosis.

Functional hemispherectomy

This procedure is a modern adaptation of the radical hemispherectomy in which one brain hemisphere is removed to prevent the spread of seizures from one brain hemisphere to the other. In the functional version only a part of the hemisphere is removed but the connections to the other brain hemisphere are cut through. This procedure is only performed on a small group of patients under the age of 13 that have severe damage or malformation of one hemisphere, patients with Sturge Weber syndrome or patients with Rasmussen's encephalitis. The functional hemispherectomy can achieve long-term seizure freedom in over 80% of patients however often at the price of hemiplegia and hemianopsy. The death rate is around 1 to 2% and 5% of patients develop a hydrocephalus that needs to be treated with a shunt.JOURNAL, Schramm, J., Kuczaty, S., Sassen, R., Elger, C. E., Lehe, M. von, 2012-09-01, Pediatric functional hemispherectomy: outcome in 92 patients, Acta Neurochirurgica, en, 154, 11, 2017–2028, 10.1007/s00701-012-1481-3, 22941395, 0001-6268,

Multiple subpial transection

Multiple subpial transection (MST) is a palliative procedure that is considered when an epileptic focus can be identified but cannot be removed because it is in a functionally relevant brain region- a so-called eloquent region. In an MST nerve fibers are disconnected so that seizures cannot spread from the epileptic focus into the rest of the brain. Between 60 and 70% of patients experienced a seizure reduction of over 95% after an MST and the risk for neurologic deficits is around 19%.JOURNAL, Spencer, Susan S., Schramm, Johannes, Wyler, Allen, O'Connor, Michael, Orbach, Darren, Krauss, Gregory, Sperling, Michael, Devinsky, Orrin, Elger, Christian, 2002-02-01, Multiple Subpial Transection for Intractable Partial Epilepsy: An International Meta-analysis, Epilepsia, en, 43, 2, 141–145, 10.1046/j.1528-1157.2002.28101.x, 1528-1167,

Vagus nerve stimulation

Vagus nerve stimulation (VNS) involves implanting a pacemaker-like generator below the skin in the chest area that intermittently sends electrical impulses to the left vagus nerve in the neck. The impulses are mediated to the brain by the vagus nerve and thereby help to inhibit electrical disturbances that cause seizures. The antiepileptic effect of vagus nerve stimulation increases over several months: after two years around half of VNS patients experience a reduction of their seizures by at least 50%JOURNAL, Elliott, Robert E., Morsi, Amr, Kalhorn, Stephen P., Marcus, Joshua, Sellin, Jonathan, Kang, Matthew, Silverberg, Alyson, Rivera, Edwin, Geller, Eric, Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: Long-term outcomes and predictors of response, Epilepsy & Behavior, 20, 1, 57–63, 10.1016/j.yebeh.2010.10.017, 21144802, January 2011, JOURNAL, Orosz, Iren, McCormick, David, Zamponi, Nelia, Varadkar, Sophia, Feucht, Martha, Parain, Dominique, Griens, Roger, Vallée, Louis, Boon, Paul, 2014-10-01, Vagus nerve stimulation for drug-resistant epilepsy: A European long-term study up to 24 months in 347 children, Epilepsia, en, 55, 10, 1576–1584, 10.1111/epi.12762, 1528-1167, 25231724, and after 10 years the average seizure reduction is around 75%JOURNAL, Elliott, Robert E., Morsi, Amr, Tanweer, Omar, Grobelny, Bartosz, Geller, Eric, Carlson, Chad, Devinsky, Orrin, Doyle, Werner K., Efficacy of vagus nerve stimulation over time: Review of 65 consecutive patients with treatment-resistant epilepsy treated with VNS >10years, Epilepsy & Behavior, 20, 3, 478–483, 10.1016/j.yebeh.2010.12.042, 21296622, March 2011, Furthermore, in most patients mood (VNS has a significant anti-depressent effect and is approved for depression in some countries), alertness and quality-of-life are increased significantly within the first year of vagus nerve stimulation.JOURNAL, Ryvlin, Philippe, Gilliam, Frank G., Nguyen, Dang K., Colicchio, Gabriella, Iudice, Alfonso, Tinuper, Paolo, Zamponi, Nelia, Aguglia, Umberto, Wagner, Louis, 2014-06-01, The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: The PuLsE (Open Prospective Randomized Long-term Effectiveness) trial, Epilepsia, en, 55, 6, 893–900, 10.1111/epi.12611, 1528-1167, 4283995, 24754318, JOURNAL, Vonck, Kristl, Raedt, Robrecht, Naulaerts, Joke, De Vogelaere, Frederick, Thiery, Evert, Van Roost, Dirk, Aldenkamp, Bert, Miatton, Marijke, Boon, Paul, 2014-09-01, Vagus nerve stimulation…25 years later! What do we know about the effects on cognition?, Neuroscience & Biobehavioral Reviews, 45, 63–71, 10.1016/j.neubiorev.2014.05.005, 24858008, VNS patients can induce an extra stimulation themselves with a VNS magnet when they noticed that a seizure is approaching and it has been shown that the majority of seizures can be interrupted this type of on-demand stimulation.JOURNAL, Fisher, R. S., Eggleston, K. S., Wright, C. W., 2015-01-01, Vagus nerve stimulation magnet activation for seizures: a critical review, Acta Neurologica Scandinavica, en, 131, 1, 1–8, 10.1111/ane.12288, 25145652, 1600-0404, JOURNAL, Morris, George L., Gloss, David, Buchhalter, Jeffrey, Mack, Kenneth J., Nickels, Katherine, Harden, Cynthia, 2013-01-01, Evidence-Based Guideline Update: Vagus Nerve Stimulation for the Treatment of Epilepsy, Epilepsy Currents, 13, 6, 297–303, 10.5698/1535-7597-13.6.297, 1535-7597, 3854750, 24348133, The procedure to implant a vagus nerve stimulator is very safe: no case of death related to VNS implantation surgery has ever occurred. Infection of the tissue pocket in which the generator is located that requires antibiotic treatment occurs in around 3% of patients.JOURNAL,weblink Vagus Nerve Stimulation, Side Effects, and Long-Term Safety : Journal of Clinical Neurophysiology, 5, 415–418, Journal of Clinical Neurophysiology, 18, 2016-09-08, September 2001, Ben-Menachem, Elinor, 10.1097/00004691-200109000-00005, JOURNAL, Kahlow, Hannes, Olivecrona, Magnus, Complications of vagal nerve stimulation for drug-resistant epilepsy, Seizure, 22, 10, 827–833, 10.1016/j.seizure.2013.06.011, 23867218, December 2013, The most common side effect is hoarseness or change in voice. Headaches and shortness of breath are less common. In most cases, side effects only occur during activity of the stimulation (mostly every 3 to 5 minutes) and reduce over time.JOURNAL, Vagus Nerve Stimulation, Side Effects, and Long-Term Safety : Journal of Clinical Neurophysiology, Journal of Clinical Neurophysiology, 18, 5, 415–418,weblink September 2001, Ben-Menachem, Elinor, 10.1097/00004691-200109000-00005, In most cases VNS does not replace antiepileptic medication. Patients must continue their antiepileptic medication however in many cases the dose can be reduced over time so that patients suffer less from side effects of the medication. The battery of the VNS generator can depending on the model and the settings can last between 3 and 10 years.

VNS with cardiac-based seizure detection

In 82% of epilepsy patients the heart rate increases quickly and suddenly upon a seizureJOURNAL, Eggleston, Katherine S., Olin, Bryan D., Fisher, Robert S., Ictal tachycardia: The head–heart connection, Seizure, 23, 7, 496–505, 10.1016/j.seizure.2014.02.012, 24698385, August 2014, This is known as ictal tachycardia. Ictal tachycardia is so characteristic that it can be distinguished from the slow gradual increase of heart rate that occurs during physical activity. This way in the majority of epilepsy patients seizures can be detected in the ECG. In addition to classical VNS, some new VNS generators continuously monitor heart rate and identify fast and sudden heart rate increases associated with seizures with intelligent software. Then an automatic additional stimulation can be triggered to interrupt, prevent or alleviate the seizure. This new generator type was shown to detect and treat at least four out of five seizures and 60% of seizures were shown to be interrupted with this heart-rate triggered stimulation.JOURNAL, Boon, Paul, Vonck, Kristl, Rijckevorsel, Kenou van, Tahry, Riem El, Elger, Christian E., Mullatti, Nandini, Schulze-Bonhage, Andreas, Wagner, Louis, Diehl, Beate, A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation, Seizure, 32, 52–61, 10.1016/j.seizure.2015.08.011, 26552564, 2015, The earlier in the course of the seizure the stimulation occurred the quicker the seizure ended generally seizures were shown to be reduced by around 35% by stimulationJOURNAL, Fisher, Robert S., Afra, Pegah, Macken, Micheal, Minecan, Daniela N., Bagić, Anto, Benbadis, Selim R., Helmers, Sandra L., Sinha, Saurabh R., Slater, Jeremy, 2016-02-01, Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance—The U.S. E-37 Trial, Neuromodulation: Technology at the Neural Interface, en, 19, 2, 188–195, 10.1111/ner.12376, 26663671, 5064739, 1525-1403, JOURNAL, Boon, Paul, Vonck, Kristl, Rijckevorsel, Kenou van, Tahry, Riem El, Elger, Christian E., Mullatti, Nandini, Schulze-Bonhage, Andreas, Wagner, Louis, Diehl, Beate, A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation, Seizure, 32, 52–61, 10.1016/j.seizure.2015.08.011, 26552564, 2015,


For over 100 years it has been known that a diet with a high fat content and a low carbohydrate content can reduce seizures. Radically curbing carbohydrate intake imitates starvation and forces the body to draw energy from ketone bodies that form when fat is metabolized instead of drawing its energy from sugar. This state is called ketosis and it changes several biochemical processes in the brain in a way that inhibits epileptic activity. On this basis there are several diets that are often recommended to children under 12 years old, but are also effective in adults.

Ketogenic diet

In Europe the ketogenic diet is the diet that is most commonly recommended by doctors for patients with epilepsy. In this diet the ratio of fat to carbohydrates and proteins is 4:1. That means that the fat content of the consumed food must be around 80%, the protein content must be around 15%, and the carbohydrate content must be around 5%. For comparison the average western diet consists of a carbohydrate content of over 50%. After one year on the ketogenic diet the success rate (seizure reduction over 50%) is between 30 and 50% and the dropout rate is around 45%.JOURNAL, Freeman, John M., Vining, Eileen P. G., Pillas, Diana J., Pyzik, Paula L., Casey, Jane C., Lcsw, Kelly, and Millicent T., 1998-12-01, The Efficacy of the Ketogenic Diet—1998: A Prospective Evaluation of Intervention in 150 Children,weblink Pediatrics, en, 102, 6, 1358–1363, 10.1542/peds.102.6.1358, 0031-4005, 9832569, JOURNAL, Li, Hai-feng, Zou, Yan, Ding, Gangqiang, 2013-12-01, Therapeutic Success of the Ketogenic Diet as a Treatment Option for Epilepsy: a Meta-analysis, Iranian Journal of Pediatrics, 23, 6, 613–620, 2008-2142, 4025116, 24910737, Although the ketogenic diet can be very effective some families report that it's not compatible with daily life on the long run because it's too restrictive as bread pasta and sweets are forbidden in the ketogenic diet. In puberty with increasing autonomy it can be difficult for adolescents to follow the diet strictly. For this reason a fat ratio of 3: 1 instead of 4: 1 can be recommended to make meals more palatable. Side effects of the ketogenic diet can be constipation, tiredness and after a long term diet, in one out of 20 patients, kidney stones.JOURNAL, Kossoff, Eric H., Zupec-Kania, Beth A., Rho, Jong M., 2009-08-01, Ketogenic Diets: An Update for Child Neurologists,weblink Journal of Child Neurology, en, 24, 8, 979–988, 10.1177/0883073809337162, 0883-0738, 19535814,

MCT-Ketogenic diet

In the 1960s it was discovered that when medium-chain triglycerides (MCT) fats are metabolized in the body more ketone bodies are produced then from metabolizing any other fat. Based on this mechanism the MCT ketogenic diet a modification of the ketogenic diet was developed and it has nearly replaced the classic ketogenic diet in the USA. In the MCT ketogenic diet MCT oil is added to ketogenic meals, which allows the carbohydrate content to be increased to around 15 to 20%. This way some patients find the meals more enjoyable. The success rate of the MCT ketogenic diet does not differ from the classic ketogenic diet however not all children can tolerate the necessary large amounts of MCT oil which is also very expensive.

Modified Atkins

A modified Atkins diet describes the long term practice of the first phase of the popular Atkins diet the so-called induction phase to reduce seizures through ketosis. In this diet the fat content of the nutrition is slightly lower than in the ketogenic diet at around 60%, the protein content is around 30% and the carbohydrate content is around 10% rendering the diet less restrictive and more compatible with the daily life compared to the ketogenic diet. Several studies show that the modified Atkins diet produces a similar or slightly lower seizure reduction to the ketogenic diet.JOURNAL, GHAZAVI, Ahad, TONEKABONI, Seyed Hassan, KARIMZADEH, Parvaneh, NIKIBAKHSH, Ahmad Ali, KHAJEH, Ali, FAYYAZI, Afshin, 2014-01-01, The Ketogenic and Atkins Diets Effect on Intractable Epilepsy: A Comparison, Iranian Journal of Child Neurology, 8, 3, 12–17, 1735-4668, 4135275, 25143768, Some physicians, especially in the USA, recommend the modified Atkins diet because they assume that patients will adhere to it on the long-term because it is more compatible with daily life and the meals are more enjoyable. It has also been concluded in another study that the diet is well tolerated and effective in hard to treat childhood epilepsy.JOURNAL, Kossoff, EH, McGrogan, JR, Bluml, RM, Pillas, DJ, Rubenstein, JE, Vining, EP, A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy., Epilepsia, February 2006, 47, 2, 421–4, 16499770, 10.1111/j.1528-1167.2006.00438.x,


Deep brain stimulation of the anterior nuclei of the thalamus is approved for DRE in some countries in Europe, but has been and continues to only be used in a very few patients. After 5 years of DBS a seizure reduction of 69% and a 50%-responder rate of 68% was reported in a randomized-double blinded trial.JOURNAL, Salanova, Vicenta, Witt, Thomas, Worth, Robert, Henry, Thomas R., Gross, Robert E., Nazzaro, Jules M., Labar, Douglas, Sperling, Michael R., Sharan, Ashwini, 2015-03-10, Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy, Neurology, 84, 10, 1017–1025, 10.1212/WNL.0000000000001334, 0028-3878, 4352097, 25663221, The rate of serious device related events was 34% in this study.Responsive neurostimulation (RNS) is approved for DRE in the USA and involves stimulation directly to 1 or 2 seizure foci when abnormal electrocorticographic activity is detected by the devices software. After 2 years of RNS a seizure reduction of 53% was reported in a randomized-double blinded trial as well as a rate of serious device related events of 2.5%.JOURNAL, Bergey, Gregory K., Morrell, Martha J., Mizrahi, Eli M., Goldman, Alica, King-Stephens, David, Nair, Dileep, Srinivasan, Shraddha, Jobst, Barbara, Gross, Robert E., 2015-02-24, Long-term treatment with responsive brain stimulation in adults with refractory partial seizures, Neurology, 84, 8, 810–817, 10.1212/WNL.0000000000001280, 0028-3878, 4339127, 25616485, Transcutaneous vagus nerve stimulation (tVNS) is approved for DRE in some European countries and involves externally stimulating the auricular branch of the vagus nerve in the ear. tVNS failed to demonstrate efficacy in a first randomized-double blinded trial: responder rates did not differ between active and control groups potentially indicating a placebo effect behind the 34% seizure reduction seen in the patients who completed the full follow-up period.JOURNAL, Bauer, S., Baier, H., Baumgartner, C., Bohlmann, K., Fauser, S., Graf, W., Hillenbrand, B., Hirsch, M., Last, C., Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02), Brain Stimulation, 9, 3, 356–363, 10.1016/j.brs.2015.11.003, 27033012, 2016,



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