What does uncontrolled or refractory seizures mean?
Seizures sometimes are not controlled with seizure medications. A number of different terms may be used to describe these including: “uncontrolled,” “intractable,” “refractory,” or “drug resistant.” How often does this happen?
- Studies suggest that epilepsy fails to come quickly under control with medicines in about one-third of cases, but the true frequency depends upon the definition of uncontrolled.
- Most epilepsy specialists agree that refractory epilepsy is epilepsy for which seizures are frequent and severe enough, or the required therapy for them troublesome enough, to seriously interfere with quality of life.
- However, in more recent years, the epilepsy community has recognized the need to continue striving for ‘no seizures’ and the best control possible.
- The International League Against Epilepsy (ILAE) has proposed the following definition of drug resistant epilepsy and suggests that this term be used instead of the term 'refractory epilepsy'.
- Drug resistant epilepsy occurs when a person has failed to become (and stay) seizure free with adequate trials of two seizure medications (called AEDs).
- These seizure medications must have been chosen appropriately for the person’s seizure type, tolerated by the person, and tried alone or together with other seizure medications.
What are the reasons for uncontrolled seizures?
Seizures can be uncontrolled for four broad reasons.
- The diagnosis is wrong.
- The treatment is wrong.
- Despite the best treatment, triggers or lifestyle factors may affect seizure control.
- Properly diagnosed seizures do not respond 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.
If the diagnosis is wrong, what’s causing the seizures?
Imagine coming home at night after too much partying, and finding yourself unable to unlock your front door. One possibility is that you are at the wrong house. Another is that you are using the wrong key. Or you really may be locked out. Perhaps someone inside has engaged the deadbolt. Refractory epilepsy displays three similar categories.
An incorrect diagnosis of epilepsy, going to the wrong house, 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 refractory 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
- Fainting (syncope)
- 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
- Nonepileptic (psychogenic) seizures
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.
How do I know if the treatment is wrong?
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 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 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 may do better on low doses of AEDs, which leads to less medication side effects.
- Measuring blood levels of antiepileptic drugs (AEDs) 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 AED, then adding a second will make them seizure-free only about 10% of the time. The second drug may help, but not usually to the point of complete control. 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 AEDs.
- Also, polypharmacy can lead to drug interactions that limit how well the drug may work or increases side effects of another drug.
- One way to treat refractory seizures in people taking many medications is to streamline or simplify the medicines. 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.
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 (hyperlink to importance of compliance adherence) It can make a real difference!
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.
What is true intractable or refractory epilepsy?
True intractable epilepsy is like a bar across the front door. Difficulty controlling seizures can result from not tolerating seizure medications or seizures not responding to the medicines. The “bar across the door” is keeping the medicine from working right to control seizures without side effects.
- 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. When this happens, exploring other treatments like surgery may be helpful.
- 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.
When seizures persist after at least two good trials of the proper drugs at the right dose, a person would be considered to have intractable or drug resistant epilepsy.