Epilepsy

Janet Wong, M.D.

Diagnosis

The initial evaluation should establish the seizure type(s) within the framework of the seizure
classification of the International League Against Epilepsy (2). This determination has important
implications for the selection of AEDs and requires a thorough history from the patient and
observers with close attention to descriptions of actual seizures. Many patients experience more
than one type of seizure - for example, complex partial and secondary generalized (3). Directed
questions are often necessary to probe for identification of seizure triggers such as sleep
deprivation, alcohol intake, and stress, since measures to limit exposure to these triggers may
successfully augment AED therapy.
Electroencephalograms are useful to confirm the diagnosis of epilepsy, but may be normal in
more than 50% of patients with epilepsy. Similarly, magnetic resonance imaging studies are
helpful to rule out cortical dysplasias, infarcts or tumors, but are usually normal.

Initial Treatment

Before therapy begins, the physician should enlist the cooperation of the patient and family
members in monitoring seizure frequency and severity. Encouraging the patient to track seizures,
stress, menses and medications on a calendar often helps to demonstrate whether seizures
correlate with stress or menses, and to monitor compliance with the AED regimen. In addition, if
the patient experiences potential side effects, he can record the time of day that they occur.
Complete seizure control with minimal side effects can be achieved in approximately 70% to
80% of patients with single drug therapy; combinations of AEDs enable an additional 10% to
15% of patients to achieve seizure control without significant side effects. Table 1 shows the
recommended initial treatment for the different types of seizures. If one AED is unsuccessful
because of ineffectiveness or side effects, then a second AED may be tried. In general, it is
preferable to maintain a patient on a single AED. When the :initial medication is determined to be
ineffective, the second drug should be titrated to therapeutic level or dosage before the old AED
is tapered. As previously stated, combinations of AEDs may be necessary in some patients.
Virtually all combinations of medications have been tried, though certain combinations should be
avoided, such as any combination of phenobarbital, primidone, and diazepam (all three drugs are
central nervous system (CNS) depressants).
Table 1. Recommended treatment for different seizure types

Seizure type Initial therapy Second-line or

adjunctive therapy
Primary generalized tonic-clonic Carbamazepine Primidone
seizures Phenytoin Phenobarbital
Valproate
Partial seizures with or without Carbamazepine Valproate
secondary Phenytoin Phenobarbital
Felbamate Gabapentin
Primidone
Lamotrigine
Absence seizures Ethosuximide Trimethadione
Valproate
Myoclonic seizures Valproate Clonazepam
Mixed seizures (myoclonic and
tonic-clonic)

Side effects are a major cause of medication intolerance and noncompliance. Table 2 shows the
common and rare side effects of the commonly used marketed AEDs. The contraindications for
each medication are given in the complete prescribing information for that drug.

The AEDs differ in how easily and rapidly a loading dose can be administered as shown in
Table 3. This consideration is particularly important for patients with frequent seizures. Table 3
also presents the likely mechanism of action for each AED.

Table 4 gives pharmacokinetic information, including frequency of dosing, number of days

needed to achieve steady state, and frequency of initial monitoring (serum levels, liver function
tests, renal function tests, and complete blood counts).

Noncompliance with AED Therapy

When a patient's seizures are uncontrolled, the clinician must consider the possibility that the
patient is noncompliant, which is the most common reason for incomplete seizure control or
variable side effects. Up to half of patients treated for epilepsy may not take their medications as
directed, and over half of patients seen in emergency rooms because of recurrent seizures are
noncompliant. Clinicians should suspect noncompliance if a patient denies the diagnosis of
epilepsy, has limited financial means to pay for AEDs, has difficulty tolerating side effects, or
forgets when or how to take medication because of frequent seizures or memory impairment.
Compliance decreases with increasingly long intervals between clinic visits and increasingly
complicated medication regimens. Drug levels may help to monitor compliance, but the clinician
should be aware that serum drug levels may also vary if medications are stored in or near a humid
environment, the patient takes generic medications from different manufacturers, or there is a
significant change in the patient's weight. Further, serum levels may fluctuate during the day,
particularly those for valproate (VPA).

Side Effects

For most patients, monotherapy enhances compliance, provides a wider therapeutic window,
and is more cost effective than combination therapy; ie, there are usually fewer side effects,
idiosyncratic reactions, and teratogenic effects, and no risk of AED-AED interactions. Within the
first six months of AED therapy, systemic toxicity and neurotoxicity are as likely to
contribute to medication failure as lack of efficacy. The neurotoxic effects of AEDs include
diplopia, nystagmus, dysarthria, ataxia, incoordination, tremor, sedation, mood ii alteration,
dizziness, headache, and cognitive impairment. Whether patients complain about side effects - for
example cognitive side effects - depends on the functional level of the patient.
Adding an AED to an existing AED, ie, changing a patient from monotherapy to polytherapy,
may result in increased AED side effects. For example, adding carbamazepine to phenytoin may
increase mean total phenytoin serum levels by 35% and decrease phenytoin clearance by 37%.
Other effects of adding one AED to another are outlined in Table 5.

Combinations of AEDs and other types of medications may also cause side effects. For instance,
giving propoxyphene or erythromycin to a patient who is taking carbamazepine often elevates
carbamazepine levels. The common AED - non-AED interactions are shown in Table 6.

For patients who have peak-level side effects from a particular AED, the usual strategy is to
modify the medication regimen or treatment schedule to minimize side effects, such as spreading
the dosage out over more doses through the day. The physician should attempt to correlate drug
serum levels with the patient's side effects before abandoning that medication. Specifically, levels
should be obtained when a patient is experiencing side effects and then compared with levels
when the patient is free from symptoms. Referring to the patient's seizure calendar may be helpful
to plan the timing of drug levels in order to prove a cause-and-effect relationship. Serum levels
that are associated with neurotoxicity vary from one patient to another and may occur within the
so-called "therapeutic range." Free-serum phenytoin and valproate levels have clinical significance
in managing patients with low albumin levels or patients who are taking multiple drugs that are
tightly protein-bound and should be multiplied by 10 to approximate the "effective" total serum
level. Women with menstrual exacerbation of seizures should have their serum AED levels
checked in the premenstrual period and compared with mid-cycle levels, since AED levels may
drop during the menses.
When AEDs are withdrawn, special caution is warranted. Abrupt discontinuation of an AED
may increase the risk of seizures and status epilepticus. Withdrawal from CNS depressants, such
as phenobarbital, and the benzodiazepines should be accomplished over weeks to months in order
to minimize the risk of withdrawal seizures.

In general, women who take an AED have double the risk of bearing a malformed infant.
The risk is even higher for women who take multiple AEDs or who have a personal or family
history of malformations. Features of the fetal anticonvulsant syndrome include limb
abnormalities, craniofacial abnormalities, and growth and development abnormalities. Women
planning a pregnancy should begin to take folic acid, 0.4 mg/day, before conception and
throughout pregnancy. Women with a previous pregnancy complicated by a fetal malformation,
such as a neural tube defect, should take 4 mg/day of folic acid and should probably avoid
valproate and carbamazepine. Congenital malformations have been reported in association with all
of the "older" AEDs; clinical experience with the "newer" AEDS - felbamate, gabapentin and
lamotrigine - has not been extensive enough to determine risk.

References

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

S30.
2. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on
Classification a Terminology of the International League Against Epilepsy. Epilepsia
1989;30:389-99.
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 epilep in women of childbearing age. Epilepsia 1994;35 (Suppl. 4):S19-S28.
5. Schachter SC, Shafer PO, Murphy W. Quality of life in patients with epilepsy: correlations
with employme~ seizure frequency and satisfaction with medical care. Epilepsia
1992;33:S25.
6. Devinsky O. Clinical uses of the quality-of-life in epilepsy inventory. Epilepsia 1993;34:S39-
44.
7. Schachter SC. The Brainstorms Companion: Epilepsy In Our View, New York: Raven
Press, 1995.