CHAPTER 53
DRUG TREATMENT
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Edward B. Bromfield
Treatment of epilepsy begins as soon as the diagnosis is made.
Typically, this occurs after the second unprovoked seizure, but
ancillary data, such as neuroimaging and electroencephalo-
graphic (EEG) recording, may support the diagnosis after a
single seizure (see Chapters 50 and 52). On the other hand, the
diagnosis could be inappropriate after even several seizures, if
each can be plausibly regarded as provoked or acutely sympto-
matic of another condition, as in the case of repeated episodes
of alcohol withdrawal or hypoglycemia (described as “occa-
sional seizures” in Chapter 52). Of note is that the seizure risk
in some clinical situations is sufficiently high that theoreti-
cally epilepsy could be suspected even before a single seizure
has occurred; however, one practical argument against this
approach is the observation that none of the tested antiepilep-
tic drugs reliably prevents the first seizure in this circumstance.
The mainstay of treatment is the use of antiepileptic drugs
(AEDs), although, as mentioned, these probably do not prevent
the development of epilepsy and could perhaps better be termed
“antiseizure drugs,” because they do suppress seizures in estab-
lished epilepsy; the older term anticonvulsant is no longer
widely used because of the observation that many seizures do
not involve convulsive movements. The first successful treat-
ment, bromides, was introduced in the mid-19th century but
proved to be too toxic for continued use. Phenobarbital has
been used since the early 20th century, and phenytoin, the first
AED identified by means of systematic testing, since 1938. Most
drugs introduced before 1993 were variations of barbiturate,
hydantoin, or benzodiazepine structures, but several novel
medications have been identified and marketed since then. A
relatively small number of comparative studies have failed to
demonstrate major differences in efficacy, when used in appro-
priate situations, among the many approved AEDs. There are,
however, major distinctions in common side effects, risk
of serious idiosyncratic reactions, pharmacokinetics, drug
interactions, and cost, and these differences help inform drug
choices.
Approximately half of all patients with newly diagnosed
epilepsy (58% if idiopathic, 44% if symptomatic or cryptogenic)
respond to the first well-tolerated drug administered, and about
two thirds eventually achieve complete seizure control. Any of
the remaining third, or those in whom seizure control is
achieved at the cost of unacceptable side effects, are potential
candidates for alternative therapies. These include vagus nerve
stimulation (brain stimulation is under active study); resective
brain surgery; disconnection procedures; dietary therapies,
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including variations of the ketogenic diet; and certain supple-
ments or herbal therapies.
TREATMENT WITH ANTIEPILEPTIC DRUGS
Principles of use are outlined as follows:
1. Differences among drugs in efficacy are lesser than differ-
ences in pharmacokinetics, interactions, likely adverse
effects, and cost.
2. There are several options for nearly every clinical situation.
3. Unless a rapid therapeutic effect is essential, a low starting
dosage and slow titration rate should be chosen. This is
especially true in the treatment of elderly or ill patients.
4. In general, the dosage should be increased until, after an
adequate observation period, it is established that seizures
are controlled or until dose-related side effects develop; in
the latter case, the dosage should be decreased to the previ-
ous level, and the response should be monitored. If seizures
are not controlled, another appropriate AED should be ini-
tiated and titrated up, usually while the first drug is tapered.
5. In rare cases, increases in dosage may result in worsening
of seizures. The dosage should be reduced, and the drug will
probably need to be replaced by an alternative AED.
6. For both ethical and logistical reasons, new AEDs are invari-
ably tested as adjunctive therapy in adults with medically
intractable partial seizures. Evidence of effectiveness in
other settings is generally based on smaller studies that may
or may not be well controlled, and it leads to regulatory
approval for other uses in only a minority of cases. There-
fore, off-label use is justifiable either if approved AEDs are
not successful or if the risk of using the off-label alternative
appears lower than that of the approved AED.
7. The most common drug interactions involving AEDs are
based on induction or, less commonly, inhibition of the
hepatic mixed-function oxidase or cytochrome P450 enzyme
system. As a group, the older AEDs have much stronger
effects on this system than do the newer drugs, although
several of the latter are substrates whose metabolism is
affected by addition or withdrawal of the older drugs.
8. Serum drug concentrations can be useful in verifying com-
pliance or in providing an initial target for patients with
infrequent seizures, but if used mechanically as a guide to
dosing, they can hinder rather than help in achieving the
goal of treatment: no seizures and no side effects (and ulti-
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