by Robert S. Fisher, M.D., Ph.D.
Editor-in-Chief

Seizures come under control with medicines in about 2 of 3 people with epilepsy. Seizures that do not come under control are called "intractable," or "refractory." The definition of control is variable (1). For many, one seizure a year is far too many; others are not bothered by one a week. In a general sense, seizures are refractory if they are frequent and severe enough or the required therapy for them troublesome enough, to seriously interfere with quality of life. Seizures can be uncontrolled for three broad reasons: 1. The diagnosis is wrong; 2. The treatment is wrong; 3. The seizures do not respond to the best diagnosis and treatment.

An incorrect diagnosis of epilepsy is more common than most people might think. One chart review study by Smith and colleagues in England (2) concluded that 13% of patients referred for refractory epilepsy did not have epilepsy. If seizures are not controlled, then a reasonable first question is: "Are the episodes really seizures?" A large number of conditions can imitate seizures, as discussed in the epilepsy.com video "Seizure Imitators" (3).

A second reason for uncontrolled seizures is suboptimal treatment. Some medicines are not right for some types of seizures. Carbamazepine (Tegretol), for example is usually good for treating complex partial seizures, but not absence seizures. Ethosuximide (Zarontin) is good for absence, but not complex partial seizures. Since absence and complex partial seizures can occasionally be confused with each other, there is a chance for using an ineffective medicine. Medications can be used in the wrong dose: too low to protect against seizures, or so high as to cause severe side effects. The newer seizure medicines often have fewer side effects than do the older seizure medicines. Information about the seizure medicines can be found in our seizure medications section (4).

Polypharmacy is the employment of several medications at once to treat the same condition. Some people require more than one drug to control their epilepsy, but additional AEDs rarely lead to complete freedom from seizures. Patients taking polypharmacy may have so many side effects that it is difficult to increase dosage for any of their AEDs to an effective level. Furthermore, poly-pharmacy can lead to drug interactions that limit effectiveness or increase side effects of another drug. Therefore, one good treatment for refractory seizures in people taking polypharmacy is a streamlining of medicines.

Missing medication is a cause of breakthrough seizures. Refer to epilepsy.com (5) for more information on compliance and strategies for remembering to take epilepsy medicine. It can make a real difference!

Complicating factors, such as illness, sleep deprivation or extreme stress, can make seizures more difficult to control. These again vary with the individual. Individual precipitating factors include alcohol, exercise, flashing lights or certain visual patterns, general illness, heavy breathing (hyperventilation), 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.

True intractable epilepsy can result from seizures that are "too strong" to be controlled by medication, or by intolerance of medication. Seizures that might be easy to treat with medicine become hard to treat when the most effective medicines result in allergy or intolerable side effects. Multiple drug resistance is a condition in which people are resistant to multiple medications. Some people with multiple drug resistance have a type of metabolism that quickly inactivates drugs, causing them to be less effective. Another common experience in treating refractory epilepsy is "honeymooning," or as it is officially known, developing medication tolerance. In this situation, a new drug works for a few months and then becomes ineffective. The cycle repeats with each new medication.

When confronted with refractory seizures, various courses of action become available to physicians and to patients. The doctor can reevaluate the diagnosis and the medication therapy. The person with epilepsy can consider strategies for remembering to take medications and reduction of precipitating factors, if any. People whose seizures are not under control should be referred to an Epilepsy Center. You can look up epilepsy physician specialists (6) and epilepsy centers (7) near you at epilepsy.com. An Epilepsy Center takes a comprehensive approach to medical, psychological and social problems associated with seizures.

When medications do not work, then non-medication therapy for the epilepsy can be considered. Epilepsy surgery is a reasonable option for people with refractory epilepsy, provided that the seizure origin in the brain can be localized to one region, and that region is safe to remove. Success rates for cessation or near-cessation of seizures range from about 50-90%, depending upon the cause of seizures and their brain location. Serious complications occur with about 1 in every 50 surgeries. Epilepsy surgery is elective surgery, meaning that it is a matter of personal choice, not necessity. Considerable information is available on epilepsy.com about epilepsy surgery (8, 9, 10), but this is an issue to be discussed with your medical care team.

Vagus nerve stimulation (VNS) is another option for refractory seizures. It rarely stops seizures entirely, but it provides significant help in about half of the people who try it. A stimulator is implanted under the skin of the chest and connected to the left vagus nerve in the neck. Side effects of VNS are usually mild, including hoarseness and coughing, mostly while becoming use to the stimulation. VNS also is approved by the FDA for depression that does not respond to other treatments.

The ketogenic diet is a high fat, high protein and very low carbohydrate diet, similar to the Atkins Diet used for weight loss. It is used mainly for children with uncontrolled seizures, but it has also been useful for some adults. The KD alters the chemistry of the brain in an as yet poorly understood way, but the result is fewer seizures. See our section on the Ketogenic Diet (11).

Experimental trials. If other alternatives are not attractive, then participation in an experimental trial of new medications, device or surgical procedures may be a good option (12). New therapies are developed by clinical trials. Supervision and safety controls are extensive, but there still is an element of risk and the unknown. If a trial is successful, you may receive a useful new therapy years before it becomes available to the public.

Intractable epilepsy does not always remain intractable. First, one of the treatments listed above may prove effective. Second, individuals may be able to modify precipitating factors or their lifestyle to help to control the seizures. But even in the absence of specific therapies or life changes, there is hope for improvement. Jacqueline French and associates (1) studied 246 patients from their clinic with at least one seizure per month and inadequate relief from at least two antiepileptic drugs. Over a three-year follow-up period, 5% of these patients each year became seizure-free for at least six months. Unfavorable predictors of control were chronic cognitive impairment, long history of intractable seizures and previous status epilepticus.

Refractory (uncontrolled) epilepsy is a heavy burden. A physician needs to make certain that the diagnosis of epilepsy is correct and that the proper medicines are being used in the best way for that person. The individual with epilepsy needs to look at things they can do to better control their seizures, such as remembering medicines, staying generally healthy, getting good sleep, minimizing stress and avoiding seizure-precipitating conditions. Non-drug therapies, such as epilepsy surgery, vagus nerve stimulation or experimental clinical trials, may be good options for some patients. But even when all seems hopeless for control, 5% of people (1 out of 20) with refractory epilepsy getter better each year. There are always grounds for hope. The biggest hope is for new therapies to prevent and cure epilepsy, a key mission of this website, and its parent organization The Epilepsy Therapy Project. If you can support this cause please contact us (13).

More information on intractable seizures can be found in an expanded version of this material at epilepsy.com (14). Support for this section was generously provided by an unrestricted educational grant from Ovation Pharmaceuticals and Eisai, Inc. The text was written without knowledge of who was the sponsoring agency.

Citations

1. Callaghan et al. Annals of Neurology 2007, volume 62, pages 382–389
2. Smith et al. Quarterly Journal of Medicine 1999, volume 92, pages 15–23.
3. http://www.epilepsy.com/node/978914.
4. http://www.epilepsy.com/epilepsy/seizure_medicines
5. http://www.epilepsy.com/epilepsy/medication_compliance
6. http://www.aesnet.org/go/find-a-dr/epilepsy-com
7. http://www.naeclocator.org/locator/default2.asp
8. http://www.epilepsy.com/node/283
9. http://www.epilepsy.com/node/978892
10. http://www.epilepsy.com/epilepsy/epilepsytalkradio_archives
11. http://www.epilepsy.com/epilepsy/dietary_therapies
12. http://www.epilepsy.com/clinical_trials
13. http://www.epilepsy.com/etp/donation
14. Soon an expanded discussion of refractory seizures will be up on epilepsy.com