Issues in the Treatment of Epilepsy

Authors


Address correspondence and reprint requests to Dr. I. E. Leppik at MINCEP Epilepsy Care, Department of Neurology and Pharmacy, University of Minnesota, 5775 Wayzata Boulevard, Suite 200, Minneapolis, MN 55416, U.S.A.

The ultimate determinant in the successful treatment of epilepsy is the patient's ability to take medications consistently over a long period. Although all of the available antiepileptic drugs (AEDs) are effective when prescribed for the appropriate epilepsy syndrome, they differ in their pharmacokinetic and side-effect profiles. Many studies have shown that the major reason for seizure breakthrough is noncompliance with the prescribed medication regimen (1). Patient compliance can be enhanced if medication doses are convenient, regimens are not complicated, and the AEDs are free of side effects. One study that used a computerized pill box to monitor dosing indicated that no patients were completely compliant with their medication regimen, and the occurrence of breakthrough seizures was often associated with noncompliance of just a short duration, despite many months of successful treatment (2). Medications that require only twice-a-day or once-a-day dosing are associated with higher rates of compliance than regimens that require dosing 3 or 4 times a day (3).

Another issue complicating drug therapy of epilepsy is that most AEDs have a narrow therapeutic range (4). That is, the concentrations required at the receptor site for effective seizure control may be close to the concentrations that cause side effects. Indeed, many patients with refractory epilepsy must balance between tolerable side effects and the best possible seizure control. Medications that have a broader therapeutic index will be easier to use and are more likely to be taken as prescribed.

With the addition of levetiracetam to the armamentarium of epilepsy treatments, the physician now has an even longer list of drugs from which to choose (Table 1). In general, there are standard drugs, such as carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA), which were all approved before 1980. Then there is a 15-year gap, from 1978 to 1993, before felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), and tiagabine (TGB) were approved. Recently, oxcarbazepine (OCBZ), zonisamide (ZSM), and levetiracetam became available in the United States. The challenge to physicians is choosing the most appropriate drug for each individual patient.

Table 1.  Antiepileptic drugs marketed in the United States
Antiepileptic drugYear marketed
  1. Mephobarbital (1935), mephenytoin (1947), paramethadione (1949), phenacemide (1951), phensuximide (1953), methsuximide (1957), ethotoin (1957), and clorazepate (1981) have either been withdrawn or are rarely used because of toxicity or lack of efficacy.

Phenobarbital1912
Phenytoin1938
Primidone1952
Ethosuximide1960
Diazepam1963
Carbamazepine1974
Clonazepam1975
Valproate1978
Felbamate1993
Gabapentin1993
Lamotrigine1994
Topiramate1996
Fosphenytoin1996
Tiagabine1997
Levetiracetam1999
Oxcarbazepine2000
Zonisamide2000

Adverse effects can be categorized as pharmacologically related or idiosyncratic. The pharmacologically related side effects of AEDs usually involve the central nervous system (CNS). Very specific profiles are usually seen for specific AEDs. PHT and CBZ, both active at the sodium channel, have ataxia as a prominent feature. Barbiturates and benzodiazepines (BZDs) cause sedation and somnolence. VPA may cause tremor. TPM has been associated with decreased verbal fluency. In addition to side effects related to the CNS, AEDs may have more general side effects (Table 2)(5,6). Idiosyncratic side effects are not dose dependent, are rare, and involve toxicity of various organ systems, including the bone marrow and the liver. Teratogenicity is a major issue for women with epilepsy who are of childbearing potential. If choices are to be made in women who intend to have families, one should approach the AED selection with the view of selecting the least teratogenic agent. (See article by Dr. Jacqueline French included in this supplement, “Use of Levetiracetam in Special Populations.”)

Table 2.  Non-CNS side effects of antiepileptic drugs (5,6)
  • CNS, central nervous system; AED, antiepileptic drug

  • a

     Information on zonisamide and weight loss can be found in reference 6.

  • b

     Epoxides, -arene oxides, -enes.

SystemicWeight gainGabapentin
  Valproate
 Weight lossFelbamate
  Topiramate
  Zonisamidea
HepaticEnzyme inductionSee Table 3
 Enzyme inhibitionSee Table 3
 HepatitisAll AEDs metabolized by the liver, but especially felbamate and valproate
HematopoieticAplastic anemia,
 agranulocytosis
Felbamate
All others with reactive metabolitesb
 ThrombocytopeniaValproate
PancreasPancreatitisValproate
 Inhibited insulin releasePhenytoin
 Increased insulin effectTopiramate
ConnectiveGingival hyperplasiaPhenytoin
 tissueLupus erythematosusPhenytoin
 Dupuytren's contracturePhenobarbital
RenalRenal calculiTopiramate
  Zonisamide
 HyponatremiaCarbamazepine
  Oxcarbazepine
SkinMinor rashCarbamazepine
  Phenytoin
  Phenobarbital
 Stevens–Johnson
 syndrome
Lamotrigine, all other AEDs with reactive metabolitesb
 Hair lossValproate
 HirsutismPhenytoin
ReproductiveTeratogenicityValproate
 issues Carbamazepine
  Phenytoin
  Phenobarbital
  (Newer AEDs may be safer)
 Polycystic ovariesValproate
 Hormonal contraceptive
 failure
All AEDs that induce the CYP enzymes
 Reduced libidoPhenobarbital
SkeletalOsteoporosisPhenytoin
GastrointestinalNausea, vomitingCarbamazepine
  Phenytoin
  Valproate
 DiarrheaValproate

In addition, drug therapy can be complicated by drug interactions. This will be the case for AEDs interacting with AEDs in patients with intractable epilepsy; AEDs that are not metabolized by the liver will be much easier to use. One must not forget that the elderly will constitute an increasingly large proportion of the population with epilepsy. These patients often receive other medications in addition to AEDs and may be vulnerable to drug–AED interactions. (See article by Dr. Jacqueline French included in this supplement, “Use of Levetiracetam in Special Populations.”) To avoid pharmacokinetic interactions, one must know the metabolic pathways for each AED to make the selection most appropriate for each patient (Table 3)(5). Again, AEDs with no hepatic elimination pathways and no or low protein binding will be easier to use and safer, as drug–drug interactions are avoided, and the possibility of inadvertent subtherapeutic or toxic levels is limited. A great deal of information regarding elimination pathways and the role of isoenzymes has been recently elucidated. One must be aware of the specific isoenzymes involved for each AED (Table 3).

Table 3.  Elimination pathways and effect on hepatic enzymes of antiepileptic drugs (5)
AEDMajor hepatic enzymesRenal eliminationHepatic enzymes
InducedInhibited
  1. GT, glucuronosyltransferase; CYP, cytochrome P450 isoenzyme system; AED, antiepileptic drug.

CarbamazepineCYP 3A4; 1A2; 2C8<1%CYP 1A2; 2C; 3A; GTNone
FelbamateCYP 3A4; 2E1; other50%CYP 3A4CYP 2C19
GabapentinNoneAlmost completelyNoneNone
LamotrigineGT10%GTNone
LevetiracetamNoneAlmost completelyNoneNone
Oxcarbazepine
 MHD (active
 oxcarbazepine metabolite)
Cytosolic system1%
27%
CYP 3A4/5CYP 2C19
PhenobarbitalCYP 2C9; other25%CYP 1A2; 2C; 3A; GTNone
PhenytoinCYP 2C9; 2C195%CYP 1A2; 2C; 3A; GTCYP 2C9
TiagabineCYP 3A42%NoneNone
TopiramateNot known65%CYP 3ACYP 2C19
ValproateGT; β oxidation2%NoneCYP 2C9; GT; epoxide hydrolase
ZonisamideCYP 3A435%NoneNone

To achieve the best outcomes in the treatment of epilepsy, the following are required of a medication: (a) efficacy; (b) lack of neurotoxicity at effective doses; (c) lack of systemic toxicity (i.e., teratogenicity and idiosyncratic effects); and (d) ease of use (convenient dosing schedule and lack of drug interactions).

Over the last 15 years, a number of studies have used placebo controls to determine the effectiveness of the new AEDs for reducing the frequency of partial seizures. Although these studies did not make direct comparisons between AEDs, a meta-analysis of 28 clinical trials representing 3,883 randomized patients has shown that in terms of efficacy for partial seizures, there is no statistical difference in the responder rates between the new AEDs [GBP, LTG, TGB, TPM, vigabatrin (VGB), and ZSM](7).

Although comparative placebo-controlled studies are not available for the older medications, a study by the Veterans Affairs Epilepsy Cooperative Group comparing PHT, phenobarbital (PB), primidone (PRM), and CBZ showed no significant difference in terms of effectiveness in seizure control. However, side effects caused discontinuation of PB and PRM more often than CBZ and PHT (8). In addition, a second study from the VA Cooperative Group showed that CBZ and VPA were similarly effective for the treatment of generalized partial seizures, with CBZ having a slight edge for the treatment of complex partial seizures (9).

Thus, in terms of efficacy, there appears to be no major difference among AEDs in the treatment of partial seizures. However, the effectiveness of AEDs varies by seizure type, and thus, studies of partial seizures do not fully illuminate the clinical spectrum of activity of each drug. For example, VPA and CBZ, although effective against partial seizures, differ greatly in their effectiveness against absence seizures, the former being very effective, and the latter possibly worsening the seizures (10).

For physicians to make the best choices for their patients, thorough knowledge of the properties of the available AEDs is essential. These include pharmacokinetic profile, safety parameters, and the efficacy profile for the epilepsy syndrome. It is becoming increasingly clear that because epilepsy is a heterogeneous disorder, certain classes of medications may be more effective for certain types of epilepsy. For example, although VPA may not be as effective for localization-related epilepsy as CBZ, it is very effective in syndromes such as juvenile myoclonic epilepsy (11). Some medications may worsen certain seizure types in epilepsy syndromes. For example, some of the seizures of the Lennox–Gastaut and juvenile myoclonic epilepsy syndromes may be worsened by PHT or CBZ (11). Thus, treating physicians must know the characteristics of the specific drugs and of the epilepsy syndromes of their patients.

OLDER ANTIEPILEPTIC DRUGS

Phenobarbital

PB was introduced into clinical practice in 1912 (10). It never underwent the Food and Drug Administration (FDA) approval process, because it was introduced before those mechanisms were in place. It is currently of limited use in the United States, mostly because of its sedative and depressive side effects. Nevertheless, it is quite an effective AED and is widely used in regions of the world where cost is a major factor. Because of its long half-life, it can be dosed once in a 24-h interval and often is dosed at night to accommodate, in some part, its sedative side effect. It has a relatively good safety profile with regard to idiosyncratic reactions. Although PB has been implicated in causing birth defects, it has not been labeled with a specific Pregnancy Category in the Physicians' Desk Reference (PDR) (12).

Phenytoin

PHT was introduced into clinical practice in 1938 (10) after extensive animal testing and was the first AED to undergo FDA-mandated tests of safety in animals. It is quite effective for localization-related epilepsies, but it may aggravate certain types of seizures in the Lennox–Gastaut syndrome (11). It has, for many years, been the most widely used AED in the United States. In general, it has a good safety profile, although skin rash may be seen in ∼8% of patients (13). Rare but serious adverse events include hepatitis, systemic lupus erythematosus, and Stevens–Johnson syndrome (10).

PHT may also be associated with mild-to-moderate cognitive side effects, especially in doses in the higher therapeutic range. It has a relatively narrow therapeutic range, with the generally accepted values of 10–20 μg/ml being the usual effective range. Concentrations >30 μg/ml are often associated with side effects involving the central nervous system. The teratogenic effect of PHT has been the subject of much controversy. However, a recently published study which included 151 births to mothers with PHT monotherapy showed that this therapy was not associated with an increased risk of major malformations (14). PHT is not labeled with a specific Pregnancy Category in the PDR, although caution for use is expressed (12).

PHT is highly protein bound, is extensively metabolized via hepatic P450 enzymes (CYP 2C9 and CYP 2C19), and consequently interacts with many drugs, including other AEDs (5). The potential of PHT for drug interaction as well as its nonlinear kinetics must be carefully considered before initiating therapy or adjusting dosage level (10). In general, PHT should be dosed as 100–300 mg daily in adults, 4–8 mg/kg in children, and 3–4 mg/kg in elderly patients. These doses typically put individuals into the therapeutic range, although a few individuals may have excessively high blood levels at the standard doses because of slow metabolism. The nonlinear kinetics of PHT complicates its dose adjustments, so very small percentage increases must be used when the blood levels are in the therapeutic range, and blood-level monitoring is necessary. Because of its relatively long half-life, PHT can be dosed once or twice a day.

Primidone

PRM was introduced into clinical practice in 1952 (10). It is metabolized to PB and phenylethylmalonamide and has a profile similar to that of PB in terms of effectiveness, although it is associated with higher incidences of side effects (8,10). Side effects associated with PRM are similar to those seen with PB, although some patients experience severe nausea, dizziness, and sedation early in therapy (10). Although PRM may be teratogenic, no Pregnancy Category has been specified for it in the PDR (12).

Carbamazepine

In 1974, CBZ was approved in the United States for use as an AED. Prior to this approval, it was used primarily as a treatment for trigeminal neuralgia (15). It is most efficacious for localization-related epilepsies. Like PHT, CBZ may exacerbate seizures in Lennox–Gastaut and juvenile myoclonic epilepsy syndromes (11). It is not effective in absence seizures or myoclonic seizures.

CBZ is metabolized by CYP 3A4/5 to the 10,11-epoxide, and this has raised some safety issues (16,17). CBZ has been associated with rare cases of aplastic anemia (∼5/1,000,000 patients) (10). In ∼5% of patients, a rash will develop during initiation of therapy (10). Stevens–Johnson syndrome has also been reported. Decreased serum sodium levels during prolonged treatment with CBZ have been reported. CBZ has side effects of drowsiness, dizziness, lightheadedness, nausea, and some cognitive disturbances, especially at higher doses. It also has a relatively narrow therapeutic range (with 4–12 μg/ml). CBZ is associated with a significantly increased risk of major congenital malformations (14) and is currently listed as a Pregnancy Category D drug in the PDR (12).

CBZ metabolism is autoinduced. That is, at the beginning of therapy, the hepatic metabolism is slower than it is later in therapy. This will often necessitate an increase in dose ∼3–5 weeks after initiation of therapy. CBZ interacts with a variety of drugs, including many of the AEDs (10).

Valproate

VPA received marketing approval in 1978 in the United States (10). It is effective for simple and complex absence epilepsy, generalized epilepsy, myoclonic seizures, and complex partial seizures. VPA, in general, has a broad margin of safety. However, a study by Dreifuss et al. (18) showed that as many as one in 500 children younger than 2 years may develop hepatic dysfunction when VPA is used with other AEDs. With monotherapy, the rates decrease to approximately one in 7,000. In adults, major adverse events include nausea, weight gain, alopecia, somnolence, and tremor. Cases of acute pancreatitis, including fatalities, have been reported. Of all of the widely used AEDs, VPA is associated with the highest rate of major congenital abnormalities (14). The PDR includes a black box warning regarding teratogenicity, but no Pregnancy Category has been assigned (12).

Because of some gastric irritation seen with VPA, a product with some delayed-release features, divalproex sodium, has been developed. It also is available in a sprinkle formulation. Initial doses are usually 15 mg/kg per day, increasing at 1-week intervals by 5–10 mg/kg per day until seizures are controlled or side effects preclude further increases. Higher doses may be needed if the patient is also receiving other AEDs that may increase its metabolism. VPA is an inhibitor of LTG metabolism and inhibits CBZ-10,11-epoxide metabolism.

NEWER AEDS

Felbamate

Felbamate (FBM) received U.S. marketing approval in 1993 (10). It has a rather broad spectrum of action, being approved for use as adjunctive therapy in the treatment of Lennox–Gastaut syndrome as well as localization-related epilepsies. The major concern with this drug, however, is safety. Approximately 1 year after its introduction, it was noted that an unexpectedly high number of individuals had developed aplastic anemia and hepatitis. It is now considered likely that the idiosyncratic reaction is due to a particular metabolite of FBM, which is not cleared normally in certain individuals who have a genetic deficiency in the enzyme system that is the key in the elimination of this metabolite. A urine screening test is now available for use in individuals who are not responsive to other drugs and for whom FBM may be the major drug of choice (19). This screening, however, has not yet been validated.

FBM use is complicated by a number of drug–drug interactions. It inhibits PHT metabolism, so PHT doses must be reduced almost immediately on the introduction of FBM. The addition of FBM in patients taking VPA may cause clinically significant elevations of VPA. It can be initiated at 1,200 mg/day in polytherapy, with doses eventually needing to be titrated up to 3,600 mg/day, with reduction of concomitant AEDs throughout the titration period (19). Because of its profile, it is mostly used currently for patients with the Lennox–Gastaut syndrome and for those with epilepsies refractory to other AEDs. FBM is a Pregnancy Category C drug (12).

Gabapentin

GBP received U.S. marketing approval in 1993 (20). It is effective primarily for localization-related epilepsies. It is not effective for absence seizures or myoclonic seizures (21). It has a good safety profile, and large overdoses with minimal consequences have been reported. GBP is eliminated renally, so there are not any drug–drug interactions, and it is not protein bound. Teratogenicity has not been a major issue in animals, although limited data are available from human experience. GBP is classified as a Pregnancy Category C drug (12). It is available now in 100-, 300-, 400-, 600-, and 800-mg oral dosage forms. The usual effective dose is 900–1,800 mg/day, but doses may be higher, with ≤3,600 mg and even 6,000 mg having been reported (21).

Lamotrigine

LTG was approved in the United States in 1994 (20) and appears to have a broader spectrum of action than initially anticipated. It appears to be effective in localization-related epilepsies and in generalized epilepsies (22). The major safety concern for LTG is its association with skin rashes, which appear to be more severe than those seen with PHT and CBZ. The risk for skin rash is significantly higher when LTG is initiated in patients treated with VPA at the time of LTG initiation (23). Several studies have shown that the incidence of LTG-induced rash is higher in children than in adults (23). Metabolism of LTG is greatly inhibited by VPA.

LTG should be titrated slowly. Slow titration seems to reduce the risk for skin rashes in patients using this drug. However, the dosing becomes somewhat complicated if the patient is taking both a hepatic inducer, such as PHT or CBZ, and VPA. For example, in a patient receiving CBZ, VPA, and LTG, if the VPA is eliminated, LTG doses may need to be increased substantially. Conversely, if CBZ is eliminated, the inductive effect is lost, and doses of LTG may have to be substantially decreased to avoid toxicity. LTG is a Pregnancy Category C drug (12). It is available as 25-, 100-, 150-, and 200-mg tablets and as 5- and 25-mg chewable dispersible tablets.

Topiramate

TPM received U.S. marketing approval in 1996 (20), and it appears to have a wide spectrum of action (24). TPM is presently approved as adjunctive treatment for adults and pediatric patients aged 2–16 years with partial seizures or primary generalized tonic–clonic seizures. Its most common toxicities involve the CNS. It appears to have a higher incidence of cognitive side effects than do many of the other currently available AEDs (10). In addition, kidney stones occurred in ∼1.5% of patients during clinical trials, which is 2 to 4 times higher than expected in a similar untreated population. TPM should be initiated slowly; indeed, some physicians recommend starting with 25 mg for adults and gradually titrating the doses every 1–2 weeks until an effective dose is reached (24). The generally tolerated dose is 200–600 mg/day (10), but there is quite a bit of individual variability. TPM appears to have minimal animal teratogenicity (Pregnancy Category C) and lacks significant idiosyncratic side effects (e.g., rash, hypersensitivity, or hemotoxicity) (10,12). It is available in 25-, 100-, and 200-mg tablets.

Tiagabine

TGB was approved in the United States in 1997 for the treatment of localization-related epilepsy (20). Its mechanism is blocking γ-aminobutyric acid (GABA) reuptake, and it is effective for localization-related epilepsies. It has a favorable safety profile, and most side effects are related to the CNS. TGB is listed as a Pregnancy Category C drug (12). It does not affect the concentration of other AEDs, but its metabolism is enhanced by inducing drugs. It is available in 2-, 4-, 12-, 16-, and 20-mg tablets.

Levetiracetam

Levetiracetam was approved in November 1999 as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy (25) and is on the market in the United States as well as in other parts of the world. Studies show that levetiracetam displays potent protection in a broad range of animal models of chronic epilepsy, including both partial and primary generalized seizures. The safety profile appears to be quite good. In double-blind studies, the most commonly reported side effects have been CNS related. Levetiracetam is renally excreted and is very water soluble. It is free of any significant drug–drug interactions. It is listed as a Pregnancy Category C drug (12). Levetiracetam can be started at 1,000 mg/day, which appears to be an effective antiseizure dose and can, if needed, be titrated up to a maximal recommended daily dose of 3,000 mg within 4 weeks. It is available in 250-, 500-, and 750-mg tablets.

Oxcarbazepine

Oxcarbazepine (OCBZ) was granted final approval for marketing in 2000 (26). It has been used for more than a decade in Europe. It appears to have a broad spectrum of action and is effective for localization- related epilepsies. Its major advantage over CBZ appears to be an improved safety profile. Whereas the side effect profile of OCBZ is similar to that of CBZ, it does not undergo metabolism to 10,11-epoxide, resulting in fewer and less severe side effects (10). This lack of the 10,11-epoxide metabolite would suggest that it may have a better teratogenicity profile than CBZ; it is presently listed as Category C for use in women of childbearing potential (12). It is available in 150-, 300-, and 600-mg forms. Two hundred milligrams CBZ appears to be equivalent to 300 mg OCBZ.

Zonisamide

ZSM, available in Japan for >10 years, was approved in the United States during 2000 (26). It appears to have a broad spectrum of action, with a particular effectiveness for certain myoclonic syndromes (27). It is predominantly metabolized by the liver and has a half-life of ∼60 h, as demonstrated in pharmacokinetic studies, but as short as 30 h when used with inducing AEDs. In addition to the usual CNS effects seen with most AEDs, ZSM specifically, like TPM, is associated with an increased risk for kidney stones. ZSM is classified as a Pregnancy Category C drug (12). It is available in 100-mg tablets.

DISCUSSION

With the widely available range of AEDs, one needs to be very familiar with the various properties of these AEDs. Each patient is unique and will require an individual assessment as to which drug will be most beneficial. For women of childbearing potential, the newer AEDs that have much less animal teratogenicity than the older medications would certainly be of benefit. Ease of use also is a factor; drugs that can be started at effective doses will be easier to initiate than ones that need to be titrated slowly. Drug–drug interactions also are a major consideration. Drugs metabolized by the liver are subject to interactions with other AEDs or with drugs used for other conditions (Table 3). Side effects remain an important issue and are mostly individualized. In summary, there are now a large number of AEDs in the epileptologists' armamentarium, each with a unique profile. Therefore, optimal and cost-effective treatment necessitates extensive knowledge about the properties of each AED.