Drug Resistant Epilepsy


In the April 20, 2018, edition of the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (MMWR), Dr. Niu Tian and colleagues released a report that looked at National Health Interview Surveys data about the seizure control status of people in the U.S. who have active epilepsy. They looked at factors like whether the person had seen an epilepsy specialist or neurologist in the last year, the person was taking seizure medication, and how often the person has seizures. Read the report.

Seizures sometimes are not controlled with antiseizure medications. A number of different terms may be used to describe these including: “uncontrolled,” “intractable,” “refractory,” or “drug resistant.” How often does this happen?

Seizures can be uncontrolled for four broad reasons.

  • The diagnosis is wrong and this is not epilepsy.
  • The treatment is wrong. Some medications can worsen certain seizure types.
  • Despite the best treatment, triggers or lifestyle factors may affect seizure control. Poor compliance with medicine or factors such as severe sleep deprivation or alcohol consumption may limit how well medication works.
  • Properly diagnosed seizures sometimes do not respond even to the best medical treatment.

Not all uncontrolled seizures are considered refractory or drug resistant. For example:

  • If the diagnosis is corrected and seizures can be brought under control with a different treatment, then they would not be considered refractory.
  • If triggers of lifestyle factors could be avoided or modified preventing breakthrough seizures, then medication therapy may work better. A person in this situation would not be considered drug resistant, but different drug trials may be considered and non-drug treatments may be considered to help control seizures.

An incorrect diagnosis of epilepsy is more common than most people might think. One chart review study by Smith and colleagues in England found that 13% of patients referred for drug resistant epilepsy did not have epilepsy. If seizures are not controlled, then a reasonable first question is: “Are the episodes really seizures?”

A number of conditions can imitate seizures. Some, but certainly not all, are listed here.

Imitators of Epilepsy

All Ages Children Mainly Adults
Fainting (syncope)

Breath-holding spells

Mini-strokes (transient ischemic attacks or TIAs)

Hypoglycemia (low blood sugar)


Migraine with confusion    
Sleep disorders, such as narcolepsy and others    
Movement disorders: tics, tremors, dystonia    
Fluctuating problems with body metabolism    
Panic attacks    
Psychogenic events    

Experienced clinicians are skilled at using a combination of the medical history, the physical exam and certain laboratory tests to determine whether sudden episodes with alteration in sensation, strength, behavior or awareness are seizures or one of the imitators. But sometimes this is difficult. People have been referred to epilepsy centers for brain surgery, when their underlying condition was not epilepsy, but one of the imitators.

Another reason for uncontrolled seizures is poor or less than optimal treatment. In other words, the ‘wrong key’ is being used to unlock the door! Common reasons for suboptimal treatment are listed below.

Reasons for suboptimal treatment of seizures

  • Using the wrong medication
  • Inadequate doses of medicine
  • Polypharmacy and toxicity
  • Missing doses (poor compliance)
  • Complicating factors (illness, sleep deprivations, extreme stress)

Using the wrong medication. Many seizure medications have useful actions against a number of different seizure types. But some medicines are not right for certain types of seizures. Carbamazepine (Tegretol), for example is usually good for treating focal seizures, but not absence and myoclonic seizures. Ethosuximide (Zarontin) is good for absence, but does not help focal seizures. Since absence and focal seizures can occasionally be confused with each other, there is a chance for using the wrong medicine.

Inadequate or incorrect doses of medicine. People vary widely in their response to seizure medicines. Every medicine has a suggested dosage range, but that range is too high for some and too low for others. If a dose that is too high for an individual is used, a person will have too many side effects. A dose that is too low may lead to seizures.

  • Some people with uncontrolled seizures may become seizure free when the medication daily dosages are increased.
  • Others, like older patients, may do better on low doses of ASMs, which leads to less medication side effects.
  • Measuring blood levels of antiseizure medications (ASMs) sometimes helps to guide therapy, but levels are not as important as carefully asking about side effects and seizure control. The newer seizure medicines often have fewer side effects than the older seizure medicines.
  • Information about seizure medicines can be found here on epilepsy.com

Polypharmacy and toxicity. Polypharmacy is the use of several medications at once to treat the same condition. Some people require more than one drug to control their epilepsy, but additional medications rarely lead to complete freedom from seizures.

  • Two important studies, one by Mattson and colleagues and the other by Kwan and Brodie suggest that if a person is not seizure-free on a good dosage of a single ASM, then adding a second will make them seizure-free only about 10% of the time.
  • The success of a second medication in children is higher, approximately 30%. 
  • Two drugs have more side effects than does one drug, and three drugs more than two.
  • Patients taking polypharmacy may have so many side effects that it is often difficult for someone to tolerate a higher dose for any of their ASMs.
  • Also, polypharmacy can lead to drug interactions that limit how well the drug may work or increases side effects of another drug.
  • Patients taking polypharmacy may have so many side effects that it is often difficult for someone to tolerate a higher dose for any of their ASMs.
  • Also, polypharmacy can lead to drug interactions that limit how well the drug may work or increases side effects of another drug.
  • Sometimes it can help to streamline or simplify the medicines but this must be done under the supervision of your neurologist. Sometimes “less can be more,” especially if it lowers overall levels of side effects and allows an increase in the drug that is most effective. Making these changes can be hard, with a period of seizures and side effects during the changes, until the new and improved regimen is established.

Triggers or Lifestyle Factors

Missing doses (poor adherence or compliance). Missing medication is a cause of breakthrough seizures. Almost everyone forgets to take pills, especially if the pill schedule is complicated. In the medical field, this is called "poor compliance." Learn about the importance of adherence and ways to make taking medications easier can make a real difference! Using a pill box can improve compliance significantly and is recommended for patients of all ages. 

Complicating factors (illness, sleep deprivations, extreme stress). Complicating or precipitating factors for seizures can make them more difficult to control. These again vary with the individual. Triggers may include alcohol, exercise, flashing lights or certain patterns, general illness, heavy breathing (hyperventilation), lowering dose of medicines, taking certain medications, the menstrual cycle, missing medications, missing sleep, recreational drugs, and stress. All too often, a seizure breakthrough is preceded by one of these, or other personally relevant, factors.

If someone is having drug-resistant seizures they should be promptly assessed at a Comprehensive Epilepsy Clinic to confirm they truly have epilepsy; to ensure their epilepsy and seizure type is correctly diagnosed and the right medicines are being used; and to assess if there is a “better” treatment for their underlying type of epilepsy.

Drug-resistant epilepsy has a number of negative consequences:

  • Learning and development problems in children: Drug-resistant seizures that begin early in life are associated with high rates of learning problems and intellectual disability.
  • Epilepsy-related injury
  • Increased risk of Sudden Unexpected Death in Epilepsy (SUDEP)
  • Increased risk of emotional and behavioral problems
  • Poorer occupational outcomes
  • Increased risk of side effects to multiple antiseizure medications

Once epilepsy is drug resistant, the likelihood that it will go away is relatively low. This is particularly true if there is a known structural abnormality of the brain. In order to prevent some of the negative consequences of long-standing, poorly-controlled seizures, it is important to be assessed at a Comprehensive Epilepsy Center in a timely manner.

In some people with drug resistant epilepsy, there are effective treatment options, with a high chance of seizure freedom. These include:

  • Resective Epilepsy Surgery
    • Resective epilepsy surgery consists of removing the area of the brain that is causing the seizures. However, for a patient to be a good candidate for surgery, the following conditions have to be met: 
      • The area of the brain where seizures originate is clearly identified.
      • That area of the brain can be safely removed with surgery. In other words if the risk is greater than “minimal risk,” the patient is not a candidate.
    • The probability to achieve seizure freedom with epilepsy surgery varies depending on the structures of the brain involved. For example, patients whose seizures originate in the temporal lobe have a 50% to 70% chance of achieving seizure-freedom.
    • Today, newer, less-invasive techniques are being used in the place of resective surgery in appropriate cases. These include the use of laser, in which a laser probe burns the area of the brain causing the seizures. However, these new techniques may not work for all candidates for resective surgery.
  • Specific Metabolic Treatment
    • While metabolic causes of epilepsy are uncommon, identifying some of these conditions can lead to specific treatments to allow the body to compensate for the metabolic change.
    • Examples are treatment with a ketogenic diet for GLUT1 deficiency, treatment with pyridoxine or pyridoxal-5-phosphate for vitamin dependent epilepsies, and creatine supplementation for creatine deficiency syndromes.
  • Specific Genetic Causes
    • Identifying a specific genetic cause can help your doctor choose the best treatment for seizures.
      • For example, with SCN1A pathogenic variants, medications such as Oxcarbazepine (Trileptal), Carbamazepine (Tegretol) or Phenytoin (Dilantin) should be avoided. Whereas with other types of pathogenic variants, such as SCN2A and SCN8A variants, these medications can be very helpful.
      • Some specific treatments which target the underlying problem caused by the genetic variant are in clinical trials, and may improve learning and development as well as help with seizures.
  • Immunotherapy
    • In the last decade, the role of inflammatory processes in certain types of epilepsy has been recognized. In these cases, medications that counteract these processes have been used with success. However, they have to be used with caution as they are associated with a variety of adverse events.  

Unfortunately, for other persons with drug-resistant epilepsy, there is still no highly effective therapy for their epilepsy type or cause. In such cases, it is important to optimize seizure control, but maximize quality of life and minimize side effects of medication.

Options for the management of drug resistant epilepsy include:

  • Ongoing trials of antiseizure medications
    • All medications have potential side effects, but some people experience them more often than others, or the side effects are more bothersome. 
    • Sometimes people develop allergies to medicines or just can’t tolerate non-allergy side effects.
    • People who are very sensitive to seizure medicines are less likely to find one that they can tolerate and that will work! 
    • Seizures that might be easy to treat with medicine become hard to treat when the best medicines are off-limits.
    • Some people with multiple drug resistance have a type of metabolism that quickly inactivates or isolates drugs, causing them to be less effective. 
    • Depression and anxiety disorders can occur in one out of every 2-3 people with treatment-resistant epilepsy.
    • The existence of these conditions can interfere with the tolerance and compliance of ASM, thus affecting the treatment of seizures. Furthermore, they can worsen the quality of life of these patients, even to a greater degree than the actual seizures.
    • Furthermore, they can worsen the quality of life of these patients, even to a greater degree than the actual seizures. 
    • Another common problem is reaching a “honeymoon” state or as it is officially known, developing medication “tolerance.” In this situation, a new drug works for a few months and then seizures return. The cycle repeats with each new medication. Such patients can end up on a stressful “rotation diet” of different medicines. It is another form of drug resistance.
  • Dietary Therapy
    • The ketogenic diet can be a highly effective therapy for some persons with drug-resistant epilepsy. 
    • While this diet is most commonly used in young children, there are more palatable options such as the Modified Atkins Diet or Low Glycemic Index Treatment which can be effective for older children, teens, and adults.
  • Vagus Nerve Stimulation
    • This device is surgically implanted in the chest and often will reduce seizure frequency. A magnet can also be used to try to stop a seizure at its onset.
  • Deep Brain Stimulation or Responsive Neurostimulation
    • These stimulators involve placement of electrodes in the brain and often reduce seizure frequency. 
  • Other Palliative Surgical Options
    • For persons with recurrent drop seizures, corpus callosotomy can be very effective to reduce this seizure type. 
  • Some people with drug-resistant epilepsy may also be candidates for research studies looking at new medication or surgical trials. You can get information on possible trials by talking with your epileptologist or on ClinicalTrials.gov.
  • People with drug-resistant epilepsy face many challenges beyond just seizures.

Reviewed By:

Elaine Wirrell MD

on Monday, October 05, 2020


Epilepsy Centers

Epilepsy centers provide you with a team of specialists to help you diagnose your epilepsy and explore treatment options.


Epilepsy Medication

Find in-depth information on anti-seizure medications so you know what to ask your doctor.


Epilepsy and Seizures 24/7 Helpline

Call our Epilepsy and Seizures 24/7 Helpline and talk with an epilepsy information specialist or submit a question online.


Tools & Resources

Get information, tips, and more to help you manage your epilepsy.