Treatment : Epilepsy.com/Professionals

The strategy for designing and implementing a treatment plan begins with accurate diagnosis of the patient's seizure type(s) and measurement of seizure frequency and severity. Referral to a neurologist may be appropriate to establish the diagnosis and formulate a treatment plan, but subsequent follow-up is often managed by the primary care physician.

In evaluating the effectiveness of treatment, the clinician takes into consideration medication side effects and any psychosocial problems the patient many be having. The treatment process is more likely to be successful when the clinician has a working knowledge of available antiepileptic drugs (AEDs), their pharmacokinetics, side effects, and drug-drug interactions.

Adapted from: Schachter SC. Treatment of seizures. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 61-74.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

9 steps of treatment

An organized, systematic approach to prescribing seizure medications to patients with epilepsy is advisable. This section outlines one such approach.

1- Diagnosis

Author: SC Schachter

The first step toward initiating therapy is to establish the type or types of seizures the patient is experiencing. The classifications of seizure type and epilepsy syndrome are made primarily on clinical grounds and may be supported by laboratory, neurophysiologic, and radiographic studies. This determination has important implications for the selection of AEDs.

The International Classification of Epileptic Seizures published by the International League Against Epilepsy2 is a helpful framework to follow. If possible, determining the patient's epilepsy syndrome provides even more information about which therapies are most likely to succeed.

An accurate diagnosis requires a thorough history from the patient and observers, with close attention to descriptions of actual seizures. The patient may find it easier to express symptoms by referring to published seizure descriptions.3

If the patient is experiencing more than one type of seizure and can describe the different symptoms of each type, that may allow the clinician to better categorize the patient's seizure types and epilepsy syndrome, as well as plan the therapeutic approach more effectively.

It is often necessary to ask pointed questions to uncover seizure triggers, behaviors or environmental factors that may increase the possibility of a seizure. Common triggers include sleep deprivation, alcohol intake, stress, and other potentially modifiable factors. Measures to limit exposure to these triggers may successfully augment AED therapy.

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

2 - When to start

Author: SC Schachter

Whether antiepileptic drugs (AEDs) should be prescribed for a person reporting only one seizure requires the physician to estimate the likelihood of recurrent seizures. Up to 10% of the general population may have a single seizure, but a much smaller proportion will have recurrent seizures and therefore will need AEDs or other treatment.

One of the main factors in this decision is the type of seizure. As a rule, when a single absence seizure is reported and confirmed by the typical EEG pattern, the child usually has had many other staring spells that have not been noticed, so treatment is generally recommended.

Similarly, with partial seizures, a person commonly will have had several partial seizures, but one relatively prominent episode or convulsion has finally brought him or her to the doctor. If a partial seizure has definitely occurred, the probability of more seizures is high and most physicians recommend treatment.

The question is more difficult for a single tonic-clonic (grand mal) seizure. The chance of another seizure varies from 16% to 61%, depending on the circumstances surrounding the seizure and test results. Another seizure may be unlikely and treatment with an AED may not be needed if:

The neurologic examination shows no focal abnormalities.
Neuroimaging studies (CT, MRI) show no identifiable brain lesion.
The EEG is normal (especially with no epileptiform abnormalities).
The patient's history does not include brain insult or cognitive impairment.
There is no family history of epilepsy.
The seizure occurred during sleep.
Factors that tend to provoke seizures, such as sleep deprivation or excessive alcohol intake, can be eliminated.

The patient's wishes also must be a factor in this decision. Some patients may be willing to take the risk of having another seizure. The choice will be based on the likelihood of more seizures, the patient's lifestyle (for example, another seizure could be disastrous if the patient must drive a lot or cares for small children), and the likely side effects of the AED.

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

3 - Choosing medication

Author: SC Schachter

Complete seizure control with minimal side effects can be achieved in approximately 70% to 80% of patients using a single antiepileptic drug (AED). Of course, prescribing the most suitable AED at an appropriate dosage will increase the chances of a successful treatment outcome. See the Table: Recommended Medications for various seizure types. Extensive information on each AED is available elsewhere on this site.

If one AED is ineffective or produces intolerable side effects, a second AED may be tried. In general, it is preferable to maintain a patient on a single AED. If the initial medication is determined to be ineffective, the second drug should be titrated to therapeutic level or dosage before the first AED is tapered.

Besides the type of seizures the patient is experiencing, other factors to consider in choosing an AED include:

contraindications
likely side effects
time needed to reach a therapeutic level
frequency of dosing
forms available
mechanisms of action
drug interactions

Contraindications and side effects

The contraindications for each medication are given in the complete prescribing information for that drug. Side effects are a major cause of intolerance and noncompliance. Which side effects are most likely to trouble an individual depends on their medical history and lifestyle. See the Table: Common and Rare Side Effects of the frequently used AEDs.

Dosing considerations

AEDs differ in how easily and rapidly a loading dose can be administered, either orally or by IV. Patients with infrequent seizures can be more safely begun on an AED with a slow loading or dose initiation schedule than patients with frequent seizures. See the Table: Loading and Maintenance of AEDs doses.

Pharmacokinetic factors such as frequency of dosing, number of days needed to achieve steady state, and frequency of initial monitoring (serum levels, liver and renal function, and complete blood counts) also can play a part in the choice of an AED. Table: Pharmacokinetics. The number of days necessary to achieve steady state is particularly important in relation to the frequency of the patient's seizures. Less frequent dosing improves compliance, and the forms in which various AEDs are available may influence the choice of medication for young children or others who have difficulty swallowing tablets or capsules.

Mechanism of action also may be a consideration, especially when choosing a replacement for an AED to be stopped for ineffectiveness or trouble with side effects. Table: Mechanisms

Combination therapy

Although monotherapy is generally preferable, another 10% to 15% of patients achieve seizure control without significant side effects by using a combination of AEDs. Virtually all combinations of medications have been tried. Certain combinations should be avoided, such as any combination of the CNS depressants phenobarbital, primidone, and diazepam.

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

4 - Initiating treatment

Author: SC Schachter

After selecting an antiepileptic drug (AED) to initiate treatment, the physician can take a few other steps to maximize the likelihood of a good outcome:

Establish a dialogue
Stress compliance
Request a calendar
Follow up

Establish a dialogue

At the beginning of therapy, establish a dialogue with the patient and family that will increase their understanding of epilepsy and their ability to report important information. Epilepsy affects each patient differently and each patient has a different capacity to understand various aspects of the disorder, so you must tailor the discussion for each individual. This kind of dialogue is essential to ensure that the impact of the condition on the patient's quality of life is clear and everyone understands the expectations of the treatment plan.

Stress compliance

Stress the importance of taking the AED regularly and as prescribed. Give written instructions on how and when to take the AED. Explain the dosing regimen and any potential adverse effects or drug-drug interactions. If the patient is incapable of absorbing this information, explain it to some other responsible person, such as a family member, friend, or case manager.

Compliance with treatment is higher among patients who are well-informed and who understand the expectations of the treatment plan and the potential benefits and risks of therapy. This understanding is particularly important if the medication must be gradually increased during the initial phases of treatment.

Warn the patient not to stop taking the AED suddenly and to be sure to refill the prescription before the pills run out.

Encourage the patient to contact you before starting any other prescription or over-the-counter medication, because the serum levels of the AED could be affected.

Request a calendar

Encourage the patient and family members or friends to keep a calendar and bring it to the office for review at each visit. Items recorded should include:

seizures (time of day, symptoms, duration, and severity)
medication taken (when and how much)
possible seizure triggers (e.g., stress, sleep deprivation, menses)
symptoms that may represent side effects (type, severity, time of day)

Keeping a calendar helps to monitor and encourage compliance and may demonstrate whether seizures do correlate with factors such as stress or menses. It also helps track the patient's response to AED therapy, including any side effects.

Arrange follow-up

Schedule follow-up visits as necessary to monitor AED serum levels, blood counts, and liver and renal function, and to address any concerns about the medication or its side effects.

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

5 - Detecting noncompliance

Author: SC Schachter

Clear communication with the patient provides the basis for an effective patient-physician partnership, and noncompliance often results from a failure in communication. But even when the physician has given clear instructions and stressed the importance of following the medication regimen, noncompliance is the most common reason for incomplete seizure control or variable side effects.

Factors that increase noncompliance

Up to half of patients with epilepsy may not take their antiepileptic drugs (AEDs) as directed, and over half of the patients seen in emergency rooms because of recurrent seizures are noncompliant. Both patient-related and iatrogenic factors may be responsible.

Patient-related factors that increase noncompliance are:

denial of the diagnosis of epilepsy
limited financial means to pay for medication
difficulty tolerating side effects
frequent seizures
memory impairment

Iatrogenic factors include:

long intervals between visits to the physician
complicated medication regimens

Signs of noncompliance

Noncompliance should be suspected if there is:

an unexpected increase in the number or severity of seizures
subtherapeutic or supratherapeutic AED serum levels
a change in medical reimbursement systems

Monitoring AED levels will help determine compliance. However, patients who are compliant with the regimen also may have low or variable serum levels if:

their AEDs have been improperly stored
they take generic medications from different manufacturers
their weight changes significantly

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

6 - Managing side effects

Author: SC Schachter

Within the first 6 months of treatment with a newly prescribed antiepileptic drug (AED), systemic toxicity and neurotoxicity are as likely to contribute to AED failure as lack of efficacy. Allow sufficient time during office visits to determine whether the patient is experiencing any side effects.

The extent of some side effects can be difficult to assess. For instance, cognitive impairment (especially memory loss) is a common complaint. Neuropsychologic testing (http://www.epilepsy.com/articles/ar_1063660975.html) sometimes is needed to determine the extent of cognitive impairment and whether it is medication-related.

Check serum levels

Attempt to correlate drug serum levels with the patient's side effects before abandoning a medication. This can be done by obtaining levels when a patient is experiencing side effects and comparing them with those obtained when the patient is free from symptoms. Referring to the patient's seizure calendar may be helpful in planning the timing of drug levels, to prove a cause-and-effect relationship between peak levels and side effects. The serum levels associated with toxicity vary from one patient to another and may occur within the usual therapeutic range.

Total serum levels may be misleading. Free unbound serum levels of phenytoin and valproate should be checked in patients with low albumin levels or patients who are taking multiple drugs that are tightly protein-bound. In such patients, free levels should be multiplied by 10 to approximate the desired total serum level.

Other factors may influence serum levels:

laboratory error
generic substitution for brand-name AEDs
variable potency of pills (following improper storage, for example)
menstrual cycle (midcycle serum AED levels may be higher than during the premenstrual period or menses)

Adjust medication regimen

For patients who have peak-level side effects from an AED, the usual strategy is to modify the medication regimen or treatment schedule to minimize side effects. For example, suppose that a patient has only nocturnal seizures and takes equal doses of an AED twice a day. If the patient experiences side effects during the afternoon from the morning AED dose, those side effects may be eliminated without compromising seizure control by shifting part of the morning dose to the bedtime dose.

Spreading out the daily dosage over smaller, more frequent doses or using a slow-release form of the same medication is another possible solution to the problem of peak-level side effects.

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

7 - Interaction awareness

Author: SC Schachter

Advantages of monotherapy

For most patients, treatment with a single antiepileptic drug (AED) offers many advantages:

enhanced compliance
a wider therapeutic window
fewer side effects, idiosyncratic reactions, and teratogenic effects
cost effectiveness
no risk of AED-AED interactions

Effects of polytherapy on serum levels

One of the ways that adding an AED to an existing AED (i.e., changing a patient from monotherapy to polytherapy) may increase AED side effects is by raising serum levels of the first drug. For example, adding carbamazepine to phenytoin may increase mean total phenytoin serum levels by 35% and decrease phenytoin clearance by 37%. In other cases, the serum level of the first AED may be decreased, which could allow breakthrough seizures. See the (Table: AED-AED Interactions).

Effects of other medications on AEDs

Combinations of AEDs and other types of medications may also cause side effects or breakthrough seizures. For example:

Calcium-containing antacids may affect AED absorption
Drugs that inhibit hepatic enzymes may increase levels of hepatically metabolized AEDs
Drugs that induce hepatic metabolism may decrease AED levels

See the Table: Common AED-non-AED interactions

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

8 - Monitoring AED levels

Author: SC Schachter

What is the purpose of monitoring?

Blood tests in patients taking antiepileptic drugs (AEDs) may have several purposes:

monitoring compliance
following the results of AED dosage changes
establishing a patient's maximum tolerated serum level
looking for early signs of adverse effects (e.g., hepatic, renal, hematopoietic)

What tests should be performed?

Monitoring of AED serum levels is the most common procedure. Total serum levels can be misleading in some patients. Free unbound serum levels of phenytoin and valproate should be checked in patients with low albumin levels or patients who are taking multiple drugs that are tightly protein-bound. In such patients, free levels should be multiplied by 10 to approximate the desired total serum level.

Other tests may include measurements of electrolyte levels, liver and kidney function tests, and blood-cell counts, depending on the patient's history and the type of adverse effects reported with the AED being used.

When should blood be tested?

Baseline tests are often performed before treatment begins so that later changes can be detected.

The frequency of testing during treatment varies considerably from doctor to doctor and even country to country. In the United States, blood tests are often done routinely several weeks or months after a new drug is started. The timing of later tests depends on the patient's medical history, the drug and, most importantly, the doctor's opinion on the necessity for testing.

When is the best time to test blood levels?

Blood levels at different dosages are best compared by obtaining the level at a consistent time of day and a consistent time after the last dose of medication is taken. Routine blood levels are usually taken at the trough level, just before the medication is taken.

What are the criteria for judging treatment effectiveness?

Dosages should be changed based on clinical grounds such as seizure breakthrough or side effects, not because of the serum level. This rule applies particularly to lamotrigine, gabapentin, and felbamate, inasmuch as therapeutic ranges have not been established to have substantial clinical utility for these AEDs.

Using blood levels to check for compliance is not always reliable. Patients who are frequently noncompliant may take enough medication shortly before the test to attain a therapeutic level. In addition, trough levels fluctuate up to 15 to 20 percent in many patients who take the drug on a consistent schedule.

Other factors may influence serum levels:

laboratory error
generic substitution for brand-name AEDs
variable potency of pills (following improper storage, for example)
menstrual cycle (midcycle serum AED levels may be higher than during the premenstrual period or menses)

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

9 - Discontinuing treatment

Author: SC Schachter

Even as they are beginning therapy with antiepileptic drugs (AEDs), many patients ask how long it will be necessary to continue the treatment. This question is difficult to answer.

Most, but not all, children and adults who are seizure-free for 2 years while taking AEDs will remain so if they stop taking their medications. It is impossible to prospectively identify which patients will remain free from seizures after their AEDs are discontinued, however.

The decision whether to taper AEDs must be made on an individual basis, with consideration given to the uncertainty of the risk of seizure recurrence and the potential risk of continuing AEDs.

The principal risk of discontinuing AED therapy is recurrent seizures. This risk generally poses less of a problem for children than for adults, who may be employed and dependent on driving.

The following factors imply an increased risk for seizure recurrence:

readily identifiable brain pathology (e.g., brain tumor, congenital anomaly, cerebral contusion)
seizure onset after age 12
severe epilepsy before the initiation of AED therapy
specific epilepsy syndromes (particularly juvenile myoclonic epilepsy)
abnormal EEGs (applies only to children with idiopathic epilepsy)
multiple seizure types occurring in the same patient

The benefits of medication withdrawal include:

avoidance of side effects (such as teratogenicity, behavioral and cognitive impairment, and cosmetic effects)
reduction of secondary psychosocial issues related to the diagnosis of epilepsy, of which AEDs are a daily reminder
cost savings

How long does it take to stop?

When AEDs are withdrawn, special caution is warranted. The medication should be tapered, usually over weeks to months, rather than stopped abruptly. Abrupt discontinuation of any AED may increase the risk of seizures and status epilepticus. CNS depressants such as phenobarbital and the benzodiazepines especially may require months of very gradual withdrawal to minimize the risk of withdrawal seizures.

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

AEDs and pregnancy

Author: SC Schachter

A discussion of the teratogenicity of antiepileptic drugs (AEDs) may be found elsewhere.4 In general, women who take AEDs have double the risk of bearing a malformed infant as women who do not take AEDs. Features of the fetal anticonvulsant syndrome include limb abnormalities, craniofacial abnormalities, and growth and development abnormalities.

The risk to the fetus increases significantly if a pregnant woman takes multiple AEDs. The risk also is higher for women with a personal or family history of birth defects or miscarriages due to birth defects.

Any woman who is physically capable of becoming pregnant should be counseled on these issues and should be encouraged to take folic acid, 0.4 mg per day. Folic acid intake is particularly important before conception and should continue throughout pregnancy. Women with a previous pregnancy complicated by a fetal malformation, such as a neural tube defect, and women with a family history of birth defects should take 4 mg per day of folic acid and probably should avoid valproate and carbamazepine.

Which AEDs are safest?

Congenital malformations have been reported in association with all the older AEDs. Valproate appears to carry a particular risk of neural tube defects.

Experience with the newer AEDs (such as felbamate, gabapentin, and lamotrigine) has not been extensive enough to determine risk. Unfortunately, there are no carefully controlled studies to identify which of the AEDs are safest for the fetus. Therefore, in general, the best approach is to select an AED on a case-by-case basis, looking for one that will control seizures (especially generalized seizures) and to administer it at the minimum effective dosage. In every case, the physician must weigh the risk/benefit ratio.

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

Managing psychosocial stress

Author: SC Schachter

Pharmacotherapy is only one facet of a comprehensive approach to epilepsy management. Such factors as cognitive, physical, and psychosocial functioning may be as important to the patient's overall quality of life as seizure control.

The psychosocial aspects of epilepsy are an important component of the disorder. Patients often have major concerns about health, independence, personal growth, relationships, well-being, and security. These issues can only be appreciated and addressed if the physician attempts to uncover the psychological and social problems that adversely affect the patient's quality of life.

This process begins with taking a complete psychosocial history, including information about:

previous psychiatric illnesses or treatments
education
employment
driving
insurance
interpersonal relationships
attitude towards having epilepsy

A number of questionnaires have been developed to supplement the psychosocial history and provide a quantifiable means of assessing and following patients as pharmacotherapeutic and psychosocial interventions are implemented.5

Uncovering a source of psychosocial stress may lead to an effective strategy to reduce the impact of that stress on the patient. This reduction in turn may help reduce seizure frequency. Patients with stress-induced seizures may be candidates for stress reduction, biofeedback, or relaxation training.

Resources to meet needs

Other important adjuncts to medical therapy in selected patients may include:

support groups
individual or family counseling
legal assistance in cases of job discrimination or other legal problems
vocational training
educational guidance

The physician plays a key role in connecting the patient to the network of health care and psychosocial professionals as specific needs arise. Numerous resources are available, often through a local epilepsy association, to assist the patient. If there is no local epilepsy group, the patient should be encouraged to contact the Epilepsy Foundation.

Cultural differences

Negative preconceptions about epilepsy within certain ethnic groups may make some patients reluctant to seek treatment. The physician should be aware of and sensitive to these cultural differences. The acknowledgment of alternative forms of healing and spiritual healers may be meaningful to members of some ethnic groups and may have a place in the overall treatment plan of selected patients.

Reviewed and revised December 2003 by Steven C. Schachter, MD, Harvard Medical School

References

1. Schachter SC. Advances in the assessment of refractory epilepsy. Epilepsia. 1993;34:S24-S30.

2. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-399.

3. Schachter SC. Brainstorms: Epilepsy in Our Words. New York: Raven Press; 1993.

4. Lindhout D, Omtzigt GC. Teratogenic effects of antiepileptic drugs: implications for the management of epilepsy in women of childbearing age. Epilepsia. 1994;35 (suppl 4):S19-S28.

5. Devinsky O. Clinical uses of the quality-of-life-in-epilepsy inventory. Epilepsia. 1993;34:S39-S44.