DRUG TREATMENT

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CHAPTER 53 DRUG TREATMENT

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 electroencephalographic (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 symptomatic of another condition, as in the case of repeated episodes of alcohol withdrawal or hypoglycemia (described as “occasional seizures” in Chapter 52). Of note is that the seizure risk in some clinical situations is sufficiently high that theoretically 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 antiepileptic 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 established 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 treatment, 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 appropriate 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, including variations of the ketogenic diet; and certain supplements or herbal therapies.

TREATMENT WITH ANTIEPILEPTIC DRUGS

Principles of use are outlined as follows:

1. Differences among drugs in efficacy are lesser than differences 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 previous level, and the response should be monitored. If seizures are not controlled, another appropriate AED should be initiated 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 invariably 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. Therefore, 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 compliance 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 ultimately, optimizing quality of life). Even with the older AEDs, published therapeutic ranges have limited scientific support, and individuals may have therapeutic responses or adverse effects either below or above these ranges. For the newer AEDs, therapeutic ranges are even more provisional but are included in the following discussions for completeness.

Use of Specific Antiepileptic Drugs

AEDs may be categorized in several ways. Mechanistic classifications are logical but of limited clinical relevance, in that several drugs work by more than one mechanism and many work by mechanisms that are unknown or poorly understood. Perhaps the most useful classification concerns spectrum of action:

1. The first group of AEDs includes those that are effective against partial seizures, including simple and complex partial seizures, as well as secondarily generalized seizures. Most if not all of these also prevent primarily generalized tonic-clonic seizures; however, they are not effective against, and may worsen, other generalized seizure types, including absence and myoclonic seizures. Drugs in this class include carbamazepine, phenytoin, phenobarbital, primidone, gabapentin, oxcarbazepine, pregabalin, and tiagabine.
2. The second group includes those that can be viewed as “broad spectrum” AEDS, with activity against a variety of generalized as well as partial seizures. The traditional drug with this characteristic is valproate. There is evidence supporting a similar broad spectrum for the newer drugs lamotrigine, topiramate, levetiracetam, zonisamide, felbamate, and the older drug, methsuximide.
3. The third group includes drugs that do not easily fit in the above categories, including ethosuximide, a narrow spectrum AED with established efficacy against only typical generalized absence seizures. (Interestingly, the closely related drug methsuximide, as noted, has a broader spectrum and is effective against partial seizures as well.) There are also other, less commonly used adjunctive drugs that have different medical uses, such as acetazolamide and perhaps allopurinol. Finally, there are medications used in specific situations, including seizure clusters and status epilepticus, alcohol withdrawal and other drug-related seizures, and specific pediatric syndromes, such as infantile spasms. These include intravenous, sublingual, and rectal benzodiazepines, anesthetic agents, adrenocorticotropic hormone (ACTH), and pyridoxine.

Drugs for Partial and Tonic-Clonic Seizures

Carbamazepine

Advantages of carbamazepine are that it is considered a first-choice drug for partial and tonic-clonic seizures; it has a long history of use; and slow-release preparations allow twice-daily dosing.

Disadvantages are (1) the need to titrate slowly to avoid dose-related adverse effects and (2) pharmacokinetic interactions (cytochrome P450 enzyme inducer and substrate).

Major dose-related adverse effects include dizziness, diplopia, nausea, sedation, mild leukopenia, hyponatremia, and bradyarrhythmias (elderly). Idiosyncratic adverse effects are rash (including Stevens-Johnson syndrome), agranulocytosis, hepatic failure, pancreatitis, and lupus-like syndrome. Chronic adverse effects include osteopenia (possibly preventable with vitamin D and calcium supplementation).

Carbamazepine has teratogenic effects, including a 0.5% to 1% incidence of neural tube defects (it is unclear whether extra folate prevents these), although data have shown that the risk is not elevated very much.

The initial dosage should be 100 to 200 mg at bedtime or 100 mg twice a day, and the dosage is increased after 3 to 7 days to 200 mg twice a day. Blood values should be checked after 1 week on this dosage: carbamazepine level, complete blood cell count and differential, electrolytes (Na), and perhaps albumin and aspartate transaminase. The dosage should be increased at 3- to 7-day intervals to a level of 4 to 12 mg/L; this level should be rechecked in 4 to 6 weeks, because autoinduction may necessitate further increases. The usual maintenance dosages in adults are 600 to 1600 mg/day, up to 2400 mg/day; in children, the starting dosage is 5 to 10 mg/kg/day, and the maintenance dosage is 15 to 20 mg/kg/day, up to 30 mg/kg/day.

With regard to pharmacokinetics, the half-life is 12 to 20 hours (shorter with enzymeinducing drugs; autoinduction also occurs, with the level falling after 2 to 6 weeks on a stable dosage), and protein binding is 70% to 80%.

The usual therapeutic range is 4 to 12 mg/L.

Preparations of carbamazepine include Tegretol tablets, 100 and 200 mg; generic 200-mg tablets; a generic suspension of 100 mg/5 mL (which can solidify in tube feedings); and slow-release preparations, including Tegretol-XR in 100, 200, and 400-mg caplets and Carbatrol in 200 and 300-mg capsules.

Oxcarbazepine

Advantages of oxcarbazepine include its rapid titration, twice-daily dosing, minor interactions, and no known hepatic or hematological adverse effects; it was approved as initial monotherapy for partial seizures.

Disadvantages include dose-related effects similar to those of carbamazepine; although it is only a weak cytochrome P450 inducer, it can lower hormone (e.g., contraceptive) levels.

Oxcarbazepine is very similar chemically to carbamazepine but is not converted to epoxide metabolite, which is believed to account for many adverse effects of carbamazepine.

Major adverse effects include dose-related dizziness, diplopia, hyponatremia, somnolence, ataxia, and gastrointestinal upset. An idiosyncratic adverse effect is rash (25% cross-reactivity with carbamazepine). No chronic adverse effects are known.

Teratogenic risk with oxcarbazepine is unknown (lack of epoxide metabolite may suggest that oxcarbazepine is preferable over carbamazepine).

Initiation should be at 150 to 300 mg twice daily, increasing by 300 to 600 mg every 1 to 2 weeks to a target of 1200 to 2400 mg/day. Pediatric (age >4 years) dosages are 8 to 10 mg/kg/day, titrated to 20 to 40 mg/kg/day. Of importance is that conversion from carbamazepine can be rapid, over 1 day to 2 weeks, at a ratio of 300 mg of oxcarbazepine to 200 mg of carbamazepine.

With regard to pharmacokinetics, the half-life is 2 hours, but the drug is converted to an active monohydroxy-derivative, whose half-life is 8 to 10 hours. Protein binding is 40%.

The therapeutic range is 10 to 35 mg/L (monohydroxy-derivative).

Preparations include Trileptal tablets, 150, 300, and 600 mg, and Trileptal syrup, 300 mg/5 mL.

Phenytoin

Advantages of phenytoin are that it is arguably still a first-choice drug for partial and tonic-clonic seizures, although it is used much less in Europe than in the United States. It also has a long history of use; a long duration of action, especially with slow-release preparations (dosing is usually twice daily but can be daily); and there is a parenteral loading option. It is effective against generalized tonic as well as tonic-clonic seizures, although it is not effective against absence or myoclonic seizures.

Disadvantages include its zero-order kinetics; pharmacokinetic interactions (strong cytochrome P450 inducer); chronic cosmetic effects; and other adverse effects.

Major dose-related adverse effects are dizziness, ataxia, diplopia, and nausea. Idiosyncratic adverse effects are rash, including Stevens-Johnson syndrome; blood dyscrasias; hepatic failure; and lupus-like syndrome. Chronic adverse effects include gingival hyperplasia, hirsutism, osteopenia, pseudolymphoma, possibly lymphoma, and possibly cerebellar degeneration.

Phenytoin is teratogenic, causing a nonspecific doubling of the risk of major congenital malformations and a higher incidence of cosmetic anomalies.

In adults in nonemergency situations, the drug can be loaded orally; two doses of 500 mg or three doses of 300 mg can be taken 4 to 6 hours apart. Parenteral loading can be achieved intravenously (15 mg/kg, or 20 mg/kg for status epilepticus, not more than 50 mg/minute; the precursor drug fosphenytoin may be preferable for status epilepticus). When loading is not needed, an estimated maintenance dosage of 300 to 400 mg/day can be initiated, usually in two doses; blood levels should be checked in 1 to 2 weeks. Because of zero-order kinetics, increases must be proportionately lower as the level rises; for example, if the steady-state level on 300 mg/day is 12 mg/L, then 330 mg/day, a 10% dose increase, may be sufficient to raise the level to 15 mg/L, a 25% increase. The pediatric dosage is 4 to 5 mg/kg/day, up to 8 mg/kg or more, depending on level.

With regard to pharmacokinetics, the half-life (level-dependent) is 20 to 30 hours when the usual therapeutic range is used; protein binding is 90% (higher with renal failure or hypoalbuminemia).

The usual therapeutic range is 10 to 20 mg/L (arguably 5 to 25 mg/L).

Preparations include Dilantin tablets, 50 mg; Dilantin and generic extended-release capsules, 30 and 100 mg; a suspension, 125 mg/5 mL (must be adequately mixed in the bottle); and Phenytek capsules, 200 and 300 mg.

Gabapentin

Advantages of gabapentin include its ability to be rapidly titrated, the facts that it is relatively well tolerated and has no pharmacokinetic interactions, and its additional uses (for neuropathic pain).

Disadvantages include the recommendation of three- to four-times-daily dosing (although it can be given twice daily); it is also perceived as less efficacious than other AEDs, although data are conflicting.

Major dose-related adverse effects include sedation, dizziness, and ataxia. Idiosyncratic adverse effects include weight gain, rash (rare), behavioral changes in children, and myoclonus. There are no known chronic adverse effects.

Teratogenic risk with gabapentin is unknown.

Initiation should be at 300 mg at bedtime, increasing by 300 mg every 1 to 7 days to a target of 1800 to 3600 mg/day; in elderly patients, at 100 at bedtime or twice daily, increasing in 100 to 200-mg increments; in pediatric patients (aged >3 year), at 10 to 20 mg/kg/day, increasing to a target of 30 to 60 mg/day.

With regard to pharmacokinetics, the half-life is 5 to 7 hours (but brain kinetics are probably slower). There is no protein binding.

The provisional therapeutic range is 4 to 16 mg/L.

Preparations include Neurontin capsules, 100, 300, and 400 mg; Neurontin tablets, 600 and 800 mg; and Neurontin solution, 250 mg/5 mL. Generic gabapentin tablets are also available.

Pregabalin

Advantages of pregabalin include the lack of pharmacokinetic interactions, additional uses (for neuropathic pain), and the ability for twice-daily dosing (although three times daily may be better tolerated).

The disadvantage is that relatively slow titration is needed, to avoid sedation.

Major dose-related adverse effects include sedation, dizziness, ataxia, and blurred vision. Idiosyncratic adverse effects include weight gain, edema, and rash (rare). There are no known chronic adverse effects.

Teratogenic risk with pregabalin is unknown.

Initiation should be at 50 or 75 mg at bedtime or twice daily, increasing by a similar amount every 4 to 7 days to a target of 300 twice daily if tolerated.

With regard to pharmacokinetics, the half-life is 6 hours (but brain kinetics are probably slower). There is no protein binding.

The provisional therapeutic range is unknown.

Preparations include Lyrica capsules, 25, 50, 75, 100, 150, 200, 225, and 300 mg.

Tiagabine

Advantages of tiagabine are that it may have antianxiety or analgesic effects and it can sometimes be given twice daily.

Disadvantages include its sedating effects, the risk of nonconvulsive status epilepticus; and the fact that it is a cytochrome P450 substrate.

Major dose-related adverse effects include dizziness, somnolence, nausea, and cognitive slowing. Idiosyncratic adverse effects include rash, mood changes, and generalized nonconvulsive status epilepticus (with dosages of 48 mg/day or greater). There are no known chronic adverse effects.

Teratogenic risk with tiagabine is unknown.

Initiation should be at 4 mg at bedtime, increasing by 4 to 8 mg/day weekly to a target of 36 to 54 mg/day, taken twice or three times daily. Titration should be at 2 to 8 mg/day, increasing by 2 to 8 mg/day at weekly intervals to a target of 24 to 56 mg/day in two to four doses. In pediatric patients (aged >12 years), the initial dosage is 4 mg/day, increasing by 4 mg/week to a target of 20 to 32 mg/day.

With regard to pharmacokinetics, the half-life is 4 to 9 hours; protein binding is 96%.

The provisional therapeutic range is unknown.

Preparations include Gabitril, 2-, 4-, 12, and 16-mg tablets.

Vigabatrin

Advantages of vigabatrin are that it is very effective against partial seizures and against infantile spasms in patients with tuberous sclerosis.

A disadvantage is that it may exacerbate generalized epilepsies.

Major dose-related adverse effects include sedation, dizziness, and diplopia. Idiosyncratic adverse effects include psychiatric disturbances. Chronic adverse effects include retinal toxicity (which causes visual field defects that are detectable in high proportion with detailed testing, although they are often asymptomatic) and weight gain.

Teratogenic risk with vigabatrin is unknown.

In adults, vigabatrin should be initiated at 1 g/day and increased by 1 g/day weekly to a target of 3 to 4 g/day, taken twice daily; in children, the initial dosage should be 40 mg/kg/day, taken twice daily, and increased to a target of 40 to 150 mg/kg/day.

With regard to pharmacokinetics, the half-life is 5 to 8 hours, but the biological effect (γ-amino butyric acid transaminase inhibition) lasts days; protein binding is 0%.

The provisional therapeutic range is unknown.

Preparations include Sabril, 500-mg tablets, and a powder sachet, 500 mg.

Phenobarbital

Advantages of phenobarbital include a long half-life (daily dosing) and its low cost.

Disadvantages include cognitive and behavioral side effects and drug interactions (it is a cytochrome P450 inducer).

Major dose-related adverse effects include sedation, depression, and cognitive impairment. Idiosyncratic adverse effects include rash, hyperactivity (in children), hepatic failure (rare), and aplastic anemia (rare). Chronic adverse effects include osteoporosis and connective tissue disorders (e.g., frozen shoulder).

Phenobarbital is teratogenic, causing a two- to threefold increase over baseline in major congenital malformations.

Initiation should be at 90 to 250 mg/day; up to 20 mg/kg (<100 mg/hour for status epilepticus) can be loaded intravenously, but sedation is universal. Steady-state levels should be checked in 2 to 3 weeks (4 to 5 weeks if valproate is taken concurrently). The pediatric dosage is 2 to 7 mg/kg/day.

With regard to pharmacokinetics, the half-life is 72 to 168 hours (less in children, more when coadministered with valproate).

The usual therapeutic range is 10 to 40 mg/L (arguably 5 to 30 mg/L).

Preparations include generic tablets 15, 30, 60 (or 62.5), and 100 mg; a generic suspension, 15 or 20 mg/5 mL; and a generic parenteral formulation, 30, 60, and 130 mg/mL.

Primidone

Advantages of primidone are that the parent compound may have efficacy beyond that of phenobarbital metabolite, at least against myoclonic seizures, and that it is effective against tremor at low doses.

Disadvantages include the facts that it is possibly more sedating than phenobarbital alone; it must be taken in divided doses, usually three or four times daily; and that it is a cytochrome P450 inducer.

Primidone is metabolized to phenobarbital.

Major dose-related, idiosyncratic, and chronic adverse effects are the same as those of phenobarbital.

Primidone is teratogenic, with similar risk of major congenital malformation.

Initiation should be at 100 to 125 mg at bedtime, increasing by 125 to 250 mg every 2 to 7 days to a target of 500 to 1500 mg/day. In pediatric patients, the initial dosage is 50 mg/day, increasing to 10 to 25 mg/kg/day.

With regard to pharmacokinetics, the half-life is 6 to 22 hours (72 to 168 hours for phenobarbital metabolite); cytochrome P450 inducers promote conversion to phenobarbital.

The usual therapeutic range is 5 to 12 mg/L (10 to 40 mg/L for phenobarbital metabolite).

Preparations include Mysoline and generic tablets, 50 and 250 mg, and a generic suspension, 250 mg/5 mL.

Drugs for Generalized Seizures, Including Absence and Myoclonic, as Well as Tonic-Clonic

These also are effective against partial seizures.

Valproate

Advantages of valproate include its long history of use and the fact that it is the best established broad-spectrum AED; its concomitant effects on migraine and bipolar illness; and the fact that slow-release preparations allow twice- or possibly once-daily dosing.

Disadvantages include its acute and chronic adverse effects, particularly weight gain, and its interactions (it is a cytochrome P450 inhibitor and also competes for protein binding sites).

Major dose-related adverse effects include gastrointestinal upset, anorexia, tremor, and thrombocytopenia. Idiosyncratic adverse effects include pancreatitis (in up to 1 per 200 patients), hepatic failure (especially in infants receiving polytherapy), stupor and coma, depression, rash, hyperammonemia, and thrombocytopenia or thrombocytopathy. Chronic adverse effects include weight gain, hair loss or change in texture, and possibly polycystic ovarian syndrome.

Valproate has teratogenic effects, including a 1% to 2% incidence of neural tube defects.

Initiation should be at 250 mg twice or three times daily, increasing by 250 to 500 mg weekly to a target of 750 to 2000 mg/day (higher if the patient is also taking enzymeinducing drugs). The pediatric dosage should begin at 10 to 15 mg/kg/day, increasing by 5 to 10 mg/kg weekly to 15 to 30 mg/kg/day (maximum, 60 mg/kg/day).

With regard to pharmacokinetics, the half-life is 10 to 20 hours; up to 95% of the drug is protein bound, a lower percentage at higher doses; as a partial cytochrome P450 inhibitor, it causes elevation particularly of phenobarbital and lamotrigine levels.

The usual therapeutic range is 50 to 120 mg/L.

Preparations include Depakene or generic valproic acid capsules, 250 mg; generic syrup, 250 mg/5 mL; Depakote delayed-release tablets, 125, 250, and 500 mg; Depakote Sprinkles slow-release capsules, 125 mg; Depakote-ER extended-release capsules, 250 and 500 mg; and Depacon intravenous infusion, 100 mg/5 mL.

Lamotrigine

Advantages of lamotrigine include its broad spectrum of coverage, including Lennox-Gastaut syndrome. It is well tolerated and relatively nonsedating; it is approved as monotherapy (for partial seizures) when transitioned from an enzymeinducing AED; and it can be taken twice daily.

Disadvantages are that slow titration is needed to minimize rash risk, and patients taking lamotrigine are susceptible to enzyme induction.

Major dose-related adverse effects include dizziness, ataxia, and drowsiness (or insomnia). Idiosyncratic adverse effects include rash in 5% to 10% of patients (including a 0.1% incidence of Stevens-Johnson syndrome, which is higher in children), and hypersensitivity syndrome. No chronic adverse effects are known.

Teratogenicity is likely at higher dosages, particularly cleft palate.

Initiation with enzymeinducing AEDs should be at 50 mg/day for 2 weeks; then the dosage is increased, first to 50 mg twice daily for 2 weeks and then by 50 to 100 mg weekly to a target of 300 to 500 mg/day. Initiation with enzymeinducing AEDs plus valproate should be at 25 mg every other day for 2 weeks; then the dosage is increased, first to 25 mg every day for 2 weeks and then by 25 to 50 mg every 1 to 2 weeks to a target of 100 to 300 mg/day. For (off-label) initial monotherapy or when added to non–enzymeinducing AEDs without valproate, the initial dosage is 25 mg every other day for 2 weeks or 25 mg every day for 2 weeks, followed by 25 mg twice daily for 2 weeks and then increased by 25 to 50 mg/day every 1 to 2 weeks. For pediatric patients (aged >2 years) with enzymeinducing AEDs, the initial dosage should be 2 mg/kg/day for 2 weeks, increasing by similar amount to 5 to 15 mg/kg/day; with valproate, the initial dosage should be 0.1 to 0.2 mg/kg/day for 2 weeks, increasing by 0.5 mg/kg/day to a target of 1 to 5 mg/kg/day.

With regard to pharmacokinetics, lamotrigine is a cytochrome P450 substrate; the half-life is approximately 24 hours alone (or combination of enzymeinducing drugs and valproate), 15 hours with enzymeinducing drugs, and 60 hours with valproate and no enzymeinducing drugs.

The therapeutic range is 4 to 16 mg/L.

Preparations include Lamictal tablets, 25, 100, 150, and 200 mg, and generic chewable dispersible tablets, 5, 10, and 25 mg.

Topiramate

Advantages of topiramate are its broad spectrum of coverage, including Lennox-Gastaut syndrome; its effectiveness at low dosages in some patients; and twice-daily dosing.

Disadvantages include the need for slow titration to minimize CNS adverse effects; and its interference at high dosages with oral contraceptives in some patients.

Major dose-related adverse effects include cognitive slowing, word-finding difficulties, paresthesias, and dizziness. Idiosyncratic dose-related effects include rash, gastrointestinal upset, narrow-angle glaucoma, irritability, and metabolic acidosis. Chronic adverse effects include renal stones (in 1% to 2% of patients, a lower percentage of women) and weight loss.

Teratogenic risk with topiramate is unknown.

Initiation should be at 25 mg/day, increasing by 25 mg/day per 1 to 2 weeks to a target of 200 mg/day or higher. In pediatric patients (aged ≥2), the dosage should start at 1 to 3 mg/kg/day, increasing by similar amount every 1 to 2 weeks to 5 to 9 mg/kg/day.

Pharmacokinetics are renal and hepatic; patients are susceptible to enzyme induction; and phenytoin levels may become slightly elevated.

The therapeutic range is 5 to 20 mg/L provisionally.

Preparations include Topamax tablets, 25, 100, and 200 mg; Topamax Sprinkles capsules, 15 and 25 mg.

Levetiracetam

Advantages of levetiracetam include the fact that the starting dose is therapeutic; its efficacy; its lack of interactions; and twice-daily dosing.

Disadvantages include irritability and other less common psychobehavioral effects and the fact that its broad spectrum of coverage is not well documented.

Major dose-related adverse effects include sedation and dizziness. Idiosyncratic adverse effects include gastrointestinal intolerance, depression, and irritability. No chronic adverse effects are known, apart from clinically insignificant decreases in hemoglobin or WBC count.

The teratogenic risk of levetiracetam is unknown.

Initiation should be at 250 to 500 mg twice daily, increasing by 500 mg/day every 1 to 2 weeks to a target of 1000 to 3000 mg/day. In pediatric patients (aged >12), the dosage should start at 10 to 20 mg/kg/day, increasing by 5 to 10 mg/kg/day every 1 to 2 weeks to a target of 40 mg/kg/day.

With regard to pharmacokinetics, excretion is renal; the half-life is 6 to 8 hours, but levetiracetam is water soluble, which suggests that the brain kinetics are slower.

The therapeutic range is 10 to 40 mg/L provisionally.

Preparations include Keppra tablets, 250, 500, and 750 mg.

Zonisamide

Advantages of zonisamide include its broad spectrum of coverage and its long half-life, which allows once-daily dosing (although twice-daily dosing is recommended).

Disadvantages include the need for slow titration and sedation.

Major dose-related adverse effects include fatigue, confusion, and dizziness. Idiosyncratic adverse effects include rash (can progress to Stevens-Johnson syndrome; zonisamide probably does not cross-react with sulfa antibiotics) and hypohidrosis (in children). Chronic adverse effects include renal stones and weight loss.

Teratogenic risk with zonisamide is unknown.

The dosage should begin at 100 mg/day for 2 weeks and then increase by 100 mg every 2 weeks to a target of 400 mg/day. In pediatric patients, the dosage should begin at 2 to 4 mg/kg/day, increasing by similar amount every 1 to 2 weeks to a target of 8 mg/kg/day.

With regard to pharmacokinetics, zonisamide is a cytochrome P450 substrate; its half-life is 60 hours alone but 25 to 30 hours with enzyme inducers.

The therapeutic range is 20 to 40 mg/L provisionally.

The preparation is Zonegran, 100-mg capsules, and generic zonisamide 100-mg capsules.

Methsuximide

Advantages of methsuximide include its broad spectrum of coverage, including partial seizures, and its long half-life; dosing is usually twice daily but can be once daily.

Disdvantages include the need for slow titration, CNS side effects, and the drug’s lack of familiarity to many clinicians.

Major dose-related adverse effects include sedation and headache. Idiosyncratic adverse effects include rash (including Stevens-Johnson syndrome), psychiatric difficulties, gastrointestinal upset, lupus-like syndrome, and leukopenia. No chronic adverse effects are known.

Teratogenicity with methsuximide is unknown.

With regard to pharmacokinetics, the half-life of the active metabolite, N,N-desmethylmethsuximide, is 34 to 80 hours in adults and 16 to 45 hours in children; the level can be lowered by enzyme inducers; phenytoin levels may become elevated and carbamazepine levels decreased.

The initial dosage should be 300 mg at bedtime for 1 to 2 weeks, increasing by 300 mg every 1 to 2 weeks to a target of 900 to 1200 mg/day. In pediatric patients, the initial dosage should be 150 mg/day, increasing by 150 mg/day.

The therapeutic range is 10 to 40 mg/L (N,N-desmethylmethsuximide).

Preparations include Celontin capsules, 150 and 300 mg.

Felbamate

Advantages of felbamate include its broad spectrum of coverage, including Lennox-Gastaut syndrome. It is efficacious and nonsedating, and it is approved as initial monotherapy (for partial seizures). Dosing can be twice daily, although three times daily is usually better tolerated.

Disadvantages include drug interactions and the risk of potentially fatal aplastic anemia (1 per 5000 patients) and hepatic failure (1 per 10,000 patients).

Major dose-related adverse effects include anxiety, insomnia, fatigue, and ataxia. Idiosyncratic adverse effects include rash, aplastic anemia, and hepatic failure. One chronic adverse effect is weight loss.

Teratogenicity with felbamate is unknown.

With regard to pharmacokinetics and interactions, the half-life is 15 to 20 hours but shortened by enzyme inducers. Felbamate may act as an enzyme inhibitor, elevating phenytoin, valproate, and phenobarbital levels; however, it reduces carbamazepine levels.

The initial dosage should be 600 mg twice daily, increasing by 600 mg/day weekly to a target of 2400 to 4800 mg/day. In pediatric patients, the initial dosages should be 10 to 15 mg/kg/day, increasing to 20 to 40 mg/kg/day.

The therapeutic range is 40 to 100 mg/L provisionally.

Preparations include Felbatol tablets, 400 mg, and Felbatol suspension, 600 mg/5 mL.

Drugs with a Narrow Spectrum of Action or for Use in Specific Situations

Ethosuximide

Advantages of ethosuximide include its long half-life, which usually enables twice-daily dosing, and its effectiveness against absence seizures.

Disadvantages include narrow spectrum, with absence seizures the only well-established target.

Major dose-related adverse effects include sedation and headache. Idiosyncratic adverse effects include rash, psychiatric decompensation, gastrointestinal upset, and lupus-like syndrome. No chronic adverse effects are known.

Teratogenicity with ethosuximide is not known.

The initial dosage should be 250 mg twice daily, increasing by 250 mg/day at weekly intervals to a target of 500 to 1000 mg/day. In pediatric patients (aged >3 years), the initial dosage should be 250 mg/day, increasing by 250 mg/week to a target of 15 to 20 mg/kg/day.

With regard to pharmacokinetics, ethosuximide is metabolized hepatically, and there is no protein binding; its half-life is 30 to 60 hours.

The therapeutic range is 40 to 100 mg/L.

Preparations include Zarontin capsules, 250 mg, and Zarontin solution, 250 mg/5 mL, as well as generic 250-mg tablets.

Acetazolamide

Advantages of acetazolamide are that it is well tolerated; it is typically used adjunctively for absence seizures, but it may be used for partial seizures and intermittently for catamenial (menses-related) seizure exacerbations.

Disdvantages include its probable low efficacy; it should not be used with topiramate or zonisamide (because renal stones can result).

Major dose-related adverse effects include paresthesias, weakness, hyponatremia, and hypokalemia. Idiosyncratic adverse effects include anorexia, rash, and blood dyscrasias. One chronic adverse effect is osteomalacia.

Acetazolamide is teratogenic, likely increasing the risk of congenital malformation.

With regard to pharmacokinetics, the half-life is 2 to 13 hours.

The initial dosage should be 250 to 500 mg/day, increasing to 500 to 1000 mg/day (twice or three times daily). In pediatric patients, the initial dosage is 4 mg/kg/day, increasing over several weeks to 8 to 30 mg/kg/day.

No therapeutic range has been determined.

Preparations include Diamox tablets, 125 and 250 mg; Diamox slow-release tablets, 500 mg; suspension 50 mg/mL; and generic acetazolamide, 100-mg and 200-mg tablets.

Benzodiazepines

These differ from each other mainly by pharmacokinetics and available routes of administration. Adverse effects include mainly sedation and slowed cognition, as well as ventilatory suppression when given intravenously.

Clonazepam

This drug is used as adjunctive therapy for myoclonic and atonic seizures and less often for partial seizures. Its half-life is 20 to 40 hours, shortened by enzyme inducers; the initial dosage is 0.5 mg once or twice daily, increasing by 0.5 mg/day every 3 to 7 days to a target of 1.5 to 4 mg/day. Preparations include Klonopin or generic tablets, 0.5, 1, and 2 mg. An intravenous formulation is available in Europe.

Clorazepate

This drug is used in the same way as clonazepam (although it is approved for partial seizures). The nordiazepam metabolite half-life is 55 to 100 hours; the initial dosage is 3.75 mg twice to three times daily, increasing by 3.75 to 7.5 mg every week to a target of 15 to 45 mg/day. Preparations include Tranxene or generic tablets, 3.75, 7.5, and 15 mg, and Tranxene-CR slow-release tablets, 11.25 and 22.5 mg.

Diazepam

Diazepam is rarely used orally but widely used intravenously for status epilepticus and rectally for acute repetitive seizures. The half-life of its active metabolite, desmethyldiazepam, is 20 to 40 hours, but when the drug is given intravenously, it is redistributed out of the brain into other fatty tissues; it is also highly protein bound (99%). Therefore, when it is given intravenously, although onset of action is extremely rapid (1 to 2 minutes), duration of action is only 15 to 20 minutes. Preparations include a 5 mg/mL solution and a rectal gel (Diastat), dosages of which are according to age and weight, which is available in rectal syringes that can be adjusted to yield doses between 2.5 and 20 mg.

Lorazepam

Lorazepam is administered intravenously for status epilepticus; its onset of action (4 to 5 minutes) is slightly slower than that of diazepam, but it remains in the brain much longer, with a duration of action of 4 to 10 hours. Protein binding is 90%. Oral lorazepam is rarely used long term, but it can be given sublingually for seizure clusters, especially if the patient is too awake between seizures to tolerate rectal diazepam gel. Preparations include Ativan or generic tablets, 0.5, 1, and 2 mg, and solution, 0.5, 1, or 2 mg/mL.

Midazolam

Midazolam is administered intravenously for status epilepticus as an alternative to diazepam or lorazepam and as an infusion when status epilepticus becomes refractory. Its half-life is 1 to 2 hours. Preparations include Versed or generic vials, 1 mg/mL or 5 mg/mL.

Nitrazepam

Nitrazepam is used primarily for infantile spasms; it is not available in the United States. The dosages are 1 mg/kg in children and 0.5 mg/kg in adults, given in one or two doses.

Clobazam

Clobazam is less sedating than other benzodiazepines; it is not available in the United States. The dosage is 10 to 30 (up to 50) mg/day in one or two doses.

Fosphenytoin

A water-soluble pro-drug of phenytoin, fosphenytoin may be given more quickly (up to 150 mg phenytoin equivalents/minute in adults) and without fear of tissue necrosis in case of extravasation; it may also be given intramuscularly in nonemergency situations. Although it is not given in a propylene glycol vehicle, which has been believed to be largely responsible for the hypotensive effects of phenytoin, studies have not demonstrated a lower rate of this complication with fosphenytoin.

COMMON CLINICAL SITUATIONS AND SPECIFIC SYNDROMES

Approaches to common clinical situations and to specific syndromes are discussed as follows, presented when possible in order of the usual age at manifestation (see Chapter 52 for clinical and diagnostic considerations).

Neonatal Seizures

The first priority is to identify and treat any reversible infectious or metabolic cause. While waiting for blood test results to return, some clinicians administer in a stepwise manner 2 to 4 mL/kg of 25% glucose, 50 to 100 mg of pyridoxine (ideally during EEG recording), 1 to 2 mL/kg of 10% calcium gluconate (over minutes during electrocardiographic monitoring), and 0.1 to 0.2 mL/kg of 50% magnesium sulfate.

If ventilation and other autonomic functions are unaffected, some clinicians elect to observe or treat only with benzodiazepines. However, treatment is usually initiated with phenobarbital or phenytoin. Phenobarbital is given in two 10-mg/kg boluses at 2 to 3 mg/kg/minute, followed by additional boluses as needed. If this is unsuccessful, phenytoin may also be given in two 10-mg/kg boluses, no faster than 2 mg/kg/minute. Phenobarbital is maintained orally at 5 mg/kg/day; levels are monitored frequently because of more rapid and varied metabolisms in newborns than in older children. Variations in phenytoin absorption, as well as in metabolism, in neonates complicate its use in oral maintenance. There is experimental evidence that topiramate may have a neuroprotective role in neonatal seizure management, but recommendations must be withheld until further research.

West’s Syndrome (Infantile Spasms)

If no etiology of seizures is found, pyridoxine deficiency, a very rare but dramatically treatable cause, should be considered. Pyridoxine, 100 to 200 mg, should be administered intravenously during EEG recording; if this is the etiology, the EEG recording should improve within minutes. The mainstay of treatment, however, remains ACTH, which often produces seizure control and EEG improvement within days. ACTH may be given intramuscularly at 40 IU daily for 2 weeks and, if seizures continue, increased by 10 IU weekly until seizures are controlled or until a maximum of 80 IU/day is reached. After seizures stop, the dosage can be continued for a month and then tapered by 10 IU/week. If seizures recur, the previously effective dosage is resumed. Blood pressure, stool guaiac, electrolytes, calcium level, phosphorus level, glucose level, and signs of infection must be monitored.

Alternatives, typically used when ACTH fails or is not tolerated, include prednisone, valproate, clonazepam, lamotrigine, topiramate, felbamate, and tiagabine. Valproate can be initiated at 15 mg/kg/day in three doses and increased in 5- to 10-mg/kg/day weekly increments. Clonazepam is begun at 0.01 to 0.03 mg/kg/day in three doses, increasing by 0.25 to 0.50 mg every three days to a target of 0.1 to 0.2 mg/kg/day. The AED vigabatrin, an inhibitor of γ-amino butyric acid catabolism, is unavailable in the United States, but it can be dramatically effective, especially when the spasms are caused by tuberous sclerosis.

Lennox-Gastaut Syndrome

A variety of the broad-spectrum AEDs have shown efficacy in the treatment of Lennox-Gastaut syndrome, although responses are rarely dramatic. Valproate has traditionally been used, although the risk of hepatic failure is a concern in patients younger than 2 years, and felbamate also carries a risk of hepatic and bone marrow toxicity; topiramate and lamotrigine are likely to be safer. Clonazepam is sometimes given adjunctively, although sedation and behavioral effects limit its use. Levetiracetam, zonisamide, acetazolamide, and methsuximide are worthy of consideration but have not been studied formally. Narrow-spectrum drugs such as phenytoin and carbamazepine may be given for tonic-clonic seizures, and phenytoin may also help control tonic and perhaps atonic seizures. There is considerable evidence that the ketogenic diet can be effective in Lennox-Gastaut syndrome, with 30% to 50% of patients showing dramatic or convincing responses, and some children have been able to discontinue AEDs and show functional improvements that are maintained for a year or more, although long-term data are limited. For patients with potentially injurious drop spells, corpus callosotomy is an option, and the vagus nerve stimulator has demonstrated efficacy against Lennox-Gastaut syndrome in retrospective studies. Finally, there are anecdotal reports in which immunomodulating treatments such as ACTH, intravenous immunoglobulin, or plasmapheresis have had at least transient efficacy in treating this and other severe and refractory pediatric epilepsy syndromes.

Febrile Convulsions

Preventive treatment with standard AEDs is no longer recommended for febrile convulsions. Aside from acetaminophen for fever control and treatment of the underlying illness, treatment options after a first febrile convulsion include diazepam, 0.3 mg/kg, given orally every 8 hours at onset of subsequent fever or potential febrile illness; an alternative is rectal diazepam gel, in dosages according to the age and weight of the patient, per package insert.

Benign Epilepsy with Centrotemporal Spikes

Because of the benign course of this condition, not all pediatric neurologists treat patients with this syndrome, although most do once a secondarily generalized seizure occurs. Any AED effective against partial seizures can be used. Carbamazepine has been traditionally given, but gabapentin is also effective. Treatment can often be stopped after 1 to 2 years of seizure control, even if the EEG recording remains abnormal.

Childhood Absence Epilepsy

Ethosuximide, valproate, and lamotrigine are equally effective against absence seizures; for children with absence seizures only, however, ethosuximide is still considered the drug of choice because of a lower risk of serious adverse effects. If tonic-clonic seizures are present, then valproate or lamotrigine is preferable, because ethosuximide must be used with another AED that will treat the tonic-clonic seizures. If ethosuximide, valproate, or lamotrigine does not adequately control the absence seizures, then combinations of these may be used; topiramate, zonisamide, and levetiracetam may ultimately prove to be effective as well.

Juvenile Myoclonic Epilepsy and Related Syndromes

Valproate is still considered the first-choice drug for these conditions, although in obese men or in women, the risks of weight gain and teratogenicity may argue for an alternative. Lamotrigine is often effective, although in some patients, myoclonic seizures may not respond or may even worsen. (When phenytoin or especially carbamazepine is given, worsening of absence and myoclonic seizures is relatively common, although these drugs may be useful adjuncts for tonic-clonic seizures.) Topiramate, zonisamide, and levetiracetam may be effective alternatives as well. Finally, counseling on the need to obtain adequate sleep and to avoid use of alcohol and other psychoactive substances, as well as to maintain medication compliance, is an important part of treatment.

Alcohol and Drug Withdrawal–Related Seizures

Benzodiazepines are the mainstay of treatment for alcohol and benzodiazepine withdrawal and may also be used, along with phenobarbital, for barbiturate withdrawal. Lorazepam, 2 to 4 mg, can be administered intravenously or intramuscularly every 2 to 4 hours as needed to minimize withdrawal symptoms without causing excessive sedation. Phenytoin is typically not helpful unless status epilepticus develops. Referral to an appropriate substance abuse program should be attempted even if the chance of success is believed to be low.

LESIONAL EPILEPSY

Although structural lesions account for fewer than half of all cases of epilepsy, this proportion is higher among patients with partial epilepsies and those with a later age at onset, especially after age 60. At younger ages, pathological specimens suggest that microscopic structural abnormalities, often disorders of cortical development, underlie many cases of at least medically intractable partial epilepsy, even in those with adolescent or adult onset. Other important pathological causes include neoplasm, especially benign brain tumors such as gangliogliomas, oligodendrogliomas, dysembryoplastic neuroepithelial tumors, and astrocytomas; infections, particularly parasitic infections such as cysticercosis, but also long-term sequelae of bacterial and viral meningoencephalitis; traumatic brain injury, especially penetrating but also closed-head injury if moderate or severe; stroke, both hemorrhagic and ischemic; and congenital or acquired vascular anomalies, such as arteriovenous malformations or cavernous angiomas.

Clinical manifestations depend largely on the site of the lesion, although the correlation is far from perfect, inasmuch as the ictal discharge may start adjacent to rather than in the lesion (depending on lesion type) and may produce no symptoms or signs until it spreads within the hemisphere or even to the contralateral hemisphere. Lesions that produce either acute symptomatic seizures or later epilepsy are typically cortical or subcortical rather than deep. Frontoparietal lesions near the primary sensorimotor cortex typically produce contralateral somatosensory and motor phenomena, whereas lesions in other areas of the frontal lobe produce other manifestations: bilateral posturing if near the midline supplementary motor area, vigorous automatisms and emotional experiences with orbitofrontal and/or cingulate involvement. As a rule, frontal lobe epilepsies tend to produce frequent brief seizures that arise out of sleep and have a high propensity to generalize. Temporal lobe epilepsies differ, depending on whether the source is medial or lateral; medial temporal seizures are often characterized by a rising epigastric sensation or other autonomic disturbance. Emotional or olfactory auras may precede complex partial seizures that progress from motionless staring to oral automatisms. These complex partial seizures often last 2 to 3 minutes and are followed by postictal confusion. Lateral temporal lobe seizures are associated with auditory, language, or sometimes visual phenomena. Parietal and occipital lobe epilepsies may include partial seizures characterized by elementary or formed visual hallucinations or distortions of spatial perception, including vertigo.

Pathophysiology

The mechanisms by which structural lesions produce neuronal hyperexcitability are not well understood and probably vary for different types of lesions. Disorders of cortical development, for example, include neurons that may have abnormal receptors, channels, or connections, whereas foreign tissue and destructive lesions may injure specific neurons or neuronal populations so as to decrease inhibition or increase excitation on a neuronal or network basis. With hemorrhagic lesions, iron itself can be epileptogenic when applied to the cortex.

Prognosis

Prognoses for seizure control differ with lesion type and location. For example, mesial temporal sclerosis, a hippocampal lesion often associated with prolonged febrile convulsions in childhood and onset of partial seizures in adolescence or early adulthood, is frequently refractory to medical management but amenable to surgical treatment. Among patients with neoplasms, overall prognosis depends on likelihood of tumor growth or regrowth after resection, especially if recurrence is associated with malignant transformation, as can be seen with astrocytomas.

Diagnosis

The diagnosis of structural lesions has been revolutionized by computed tomography and especially magnetic resonance imaging, which can reliably demonstrate not only neoplasms, abscesses, and vascular anomalies but also many disorders of cortical development and gliotic lesions such as mesial temporal sclerosis.

Treatment

Any of the drugs effective against partial and tonic-clonic seizures can be used for lesional epilepsy; no drug specificity by location has been demonstrated. In the United States, carbamazepine and phenytoin are most commonly initiated, but in specific populations, valproate, lamotrigine, topiramate, gabapentin, levetiracetam, and oxcarbazepine may have advantages. (Of these, only valproate, topiramate, and oxcarbazepine are approved by the U.S. Food and Drug Administration as initial monotherapy.) It must be recognized, however, that a significant proportion of patients with lesional epilepsy do not respond to AEDs, and surgery should be strongly considered for any patient with a resectable lesion that can plausibly account for the epilepsy syndrome and whose seizures do not respond to two or more appropriate AEDs at reasonable dosages. In many cases, complete resection of the lesion alone renders the patient seizure free, and many such patients can eventually discontinue medication; it is likely that in some cases, the outcome is better if surrounding electrically abnormal tissue is also removed.

SPECIAL ISSUES RELATED TO EPILEPSY IN WOMEN

Approximately 40% of all cases of epilepsy, or approximately 1,000,000 in the United States, occur in women of childbearing age. Issues that need to be considered include effects of hormones and pregnancy on epilepsy, influence of AEDs and seizures on pregnancy and pregnancy outcome, breastfeeding, and other child care issues.

It is important to recognize that the enzymeinducing drugs carbamazepine, phenytoin, phenobarbital, primidone, and, to a lesser extent, oxcarbazepine and topiramate can increase metabolism of hormones and cause failure of oral contraceptives. If no other effective contraceptive method is available, oral contraceptives can still be used, but only in medium- or high-dose pills, and the failure rate is still above baseline.

Pathophysiology

Approximately one third of women with epilepsy, especially those with partial and perhaps temporal lobe seizures, report increased seizures shortly before menses or at ovulation. These so-called catamenial seizures probably reflect the important effects of hormones on neuronal excitability. In general, estrogens increase excitability and progesterones (particularly allopregnanolone) have inhibitory effects. The ratio of rising and falling levels of these two hormone classes probably accounts for the menstrual variation and may affect seizure fluctuations during and after menopause. On occasion, measurement of AED levels through the menstrual cycle reveals changes in absorption or metabolism that can account for the exacerbations.

The mechanisms by which AEDs cause teratogenicity are not well understood and may be different for different AEDs. One hypothesis is that oxidative injury to fetal cells results from reactive AED metabolites. Folate deficiency is also associated with several AEDs and can adversely affect fetal cell division.

Prognosis

Women with catamenial epilepsy may experience fewer seizures after menopause, although some report exacerbation during menopause. With regard to AED teratogenicity, monotherapy with the older drugs carbamazepine, phenytoin, and phenobarbital is associated with an approximate doubling of the rate of major congenital malformations from 2% to 3%, and monotherapy with valproate is associated with an approximate tripling of this rate, especially at higher doses. Because major organs are formed during the first trimester of gestation, risk of major malformations is not an issue beyond that time. The possibility of effects on neurobehavioral development posed by fetal exposure later in the pregnancy is under active investigation, and there is preliminary evidence that valproate may be problematic in this regard.

During pregnancy, an estimated one third of epileptic women experience an increase in seizures, and it is unclear whether this proportion has declined since the 1990s with increased awareness of the need to increase drug dosages as pregnancy progresses. Seizures can adversely affect pregnancy either by causing falls and other accidents or, at least in the case of convulsive seizures, by producing fetal distress.

Diagnosis

To establish the diagnosis of catamenial seizure exacerbations, the patient keeps a careful diary of seizures and menses. Close neurological and obstetrical follow-ups are needed to diagnose epilepsy-related pregnancy complications.

Treatment

Catamenial seizure exacerbations can be treated by temporarily increasing the baseline AED dosage, especially if fluctuations in levels have been demonstrated; by adding acetazolamide, 250 to 1000 mg/day for 10 to 14 days, starting at midcycle; or by administering natural progesterone lozenges, 300 to 800 mg/day, during the second half of the cycle, tapering over 2 to 3 days after onset of menses. The latter treatment is under active study; potential adverse effects include depression, breast tenderness, and hypercoagulability.

To minimize AED teratogenicity, an effective means of contraception must be used, and all women of childbearing age should be given supplemental folate; the optimal dose has not been determined, but at least 0.4 mg and perhaps as much as 5 mg should be given daily. In addition, polytherapy should be avoided whenever possible, and drug withdrawal before conception should be considered in women who have been seizure free for at least 2 years or in those for whom the diagnosis of epilepsy has not been established; in the latter case, video-EEG monitoring can enable the decision. In general, the most effective AED for the individual should be used at the lowest dosage that controls seizures, especially the secondarily or primarily generalized tonic-clonic seizures that are most likely to put both mother and fetus at risk. Women with a family history of neural tube defects should probably not use valproate or carbamazepine if pregnancy is a possibility. Knowledge of potential teratogenic effects of the newer AEDs is facilitated by use of the AED pregnancy registries, of which there are several throughout the world, organized by geographical area. In North America, the patient herself must call the toll-free number, 1-888-233-2334 (1-888-AED-AED4).

Treatment during pregnancy should include measurement of serum drug concentrations every 1 to 2 months, including free levels of highly protein-bound drugs. Total levels and, to a lesser extent, free levels tend to fall as pregnancy progresses, and dosages usually need to be increased; levels of lamotrigine and oxcarbazepine levels in particular are prone to decrease. Vitamin K, 10 to 20 mg/day, is sometimes recommended during the last month of pregnancy, especially to mothers taking enzymeinducing drugs, and vitamin K is routinely given to newborns to prevent neonatal hemorrhage. Seizures during delivery, reported to occur in 1% to 4% of women with epilepsy, may be prevented by administration of AEDs parenterally when absorption is in doubt; use of parenteral or sublingual lorazepam can also be considered, although neonatal sedation is a risk. After delivery, serum drug concentrations rise over a period of days to weeks, and dosages typically need to be decreased to avoid toxicity.

New mothers with epilepsy should be counseled to change diapers on the floor, not to bathe the baby alone, and to take other reasonable precautions consistent with the nature of the mother’s seizures. Although all AEDs can be found in breast milk, especially those that are not highly protein bound, specific risks have not been identified apart from sedation with barbiturates and benzodiazepines, and the benefits of breastfeeding probably outweigh the risks.

TOXEMIA OF PREGNANCY

Toxemia of pregnancy, or eclampsia, is a situation-related syndrome occurring in the second half of pregnancy and consisting of systemic alterations, including hypertension with edema and/or proteinuria; coagulopathy and liver dysfunction are often present. Cerebral involvement is similar to that associated with hypertensive encephalopathy and includes headache and cerebral edema, often causing visual phenomena and partial or tonic-clonic seizures (probably secondarily generalized). Hyperreflexia is usually present. The presence of coma or seizures indicates progression from preeclampsia to eclampsia.

Pathophysiology

The underlying mechanism of eclampsia is not known but may reflect alteration in endothelial function; effects on the brain are similar to those of hypertensive encephalopathy and probably relate to loss of autoregulation of cerebral blood flow, especially in posterior cerebral regions.

Prognosis

Eclampsia carries a maternal mortality rate of 1% to 2%, and there are fetal complications in one third of cases.

Diagnosis

Eclampsia is diagnosed on the basis of clinical characteristics described previously, typically by the obstetrician.

Treatment

The procedure essential to reversing the underlying eclamptic process is delivery of the baby. Seizures must still be treated, however, and in some cases, preventive treatment is justified. Traditionally, obstetricians have favored use of magnesium sulfate to treat or prevent eclamptic seizures, and neurologists have preferred the use of traditional AEDs such as phenytoin. Despite some methodological problems, studies since the 1990s have favored the obstetricians’ approach. Magnesium sulfate may be given intravenously at 20 mg of a 20% solution (4 g) over 4 minutes, with maintenance of 1 to 3 g/hour, or intramuscularly at 5 to 10 mg every 4 hrs; the dosage is titrated to a level of 3 to 5 mmol, and the patient is monitored for arreflexia and weakness that could herald ventilatory compromise. The addition of phenytoin, 15 to 20 mg/kg, can be considered, especially if seizures occur with adequate magnesium levels; lorazepam, 2 to 4 mg administered intravenously, can also be used in acute situations.

SEIZURES AND EPILEPSY IN ELDERLY PERSONS

The incidences both of acute symptomatic seizures and of epilepsy increase after age 60, and in the oldest populations, new seizures occur at annual rates exceeding 100 per 100,000. The most common cause is stroke, both ischemic and hemorrhagic, but degenerative disorders, including Alzheimer’s dementia, and both metastatic and primary brain tumors are important contributors.

Pathophysiology

The mechanisms by which these disease processes cause seizures and epilepsy depend on the type of insult and are not well understood.

Prognosis

Overall prognosis depends on the specific cause and on comorbid conditions, but in most cases, seizures respond to AED treatment at least as well as in younger individuals.

Diagnosis

Differential diagnosis of transient neurological dysfunction is similar to that discussed in Chapter 52, but in elderly patients, the likelihood of psychogenic nonepileptic seizures is lower than in younger patients, and the risk of such physiological causes as syncope or transient ischemic attack is higher. Prolonged electrocardiographic or video-EEG monitoring may be required for diagnosis. Among sleep disorders, rapid-eye-movement behavior disorder is a parasomnia that is much more common among elderly persons and is often associated with extrapyramidal movement disorders; polysomnography is required for diagnosis.

Treatment

Any of the traditional or newer AEDs discussed earlier may be used in the elderly population, but starting dosages should be lower, and dosages should be increased more slowly. In patients taking anticoagulants or other drugs whose metabolism is altered by enzyme inducers, such AEDs as phenytoin and carbamazepine must be used with caution, particularly by patients with cardiac rhythm disturbances; susceptibility to central nervous system adverse effects of barbiturates or benzodiazepines argues against use of these agents when alternatives exist. In patients taking multiple drugs for other conditions, AEDs with minimal drug-drug interactions, such as gabapentin, lamotrigine, or levetiracetam, should be strongly considered; drugs such as gabapentin and levetiracetam that are metabolized principally by the kidney should be given in dosages according to renal function, which declines with age.

MEDICATION WITHDRAWAL

In general, patients who have had no seizures for at least 2 years can be considered for medication withdrawal; a seizure recurrence risk of 20% to 40% is acknowledged. Patients who had only one seizure type that responded promptly and was controlled for many years on modest dosages of one medication have the best prognosis, especially if they have normal neurological examination findings, imaging study results, and EEG recordings. Depending on lifestyle, however, this recurrence risk may be unacceptable, and many patients elect to continue medications. Furthermore, for patients whose epilepsy can be classified as part of a specific syndrome, such as benign epilepsy with centrotemporal spikes or juvenile myoclonic epilepsy, the syndrome itself may imply a lower or higher recurrence risk than the overall statistics quoted previously.

KETOGENIC DIET

A high-fat diet that produces metabolic changes mimicking starvation can produce complete or dramatic seizure reductions in 30% to 50% of children with multiple seizure types (usually cryptogenic or symptomatic generalized epilepsy syndromes). Short-term risks include weight loss, renal stones, acidosis, hemolytic anemia, lethargy, and elevated liver function values; treatment is usually initiated in the hospital and maintained with the assistance of a dietitian. Much less information is available concerning feasibility, effectiveness, and long-term safety in adults. More palatable modifications of this high-fat, low-carbohydrate diet, such as the “low glycemic index,” South Beach, and Atkins diets, are under study.

RESECTIVE SURGERY

Among patients with medically refractory, location-related epilepsy, a significant proportion are candidates for resection of the epileptic focus. In appropriately selected patients, seizure-free rates range from 60% to 80%. The best prognosis is for patients with structural lesions, especially those with mesial temporal sclerosis. The key to a successful outcome is localization of a resectable epileptogenic region, for which a variety of structural and functional tests are used. These commonly include scalp-recorded ictal and interictal EEG recordings, usually with synchronized videography to clarify the ictal semiology; high-quality structural magnetic resonance imaging; positron emission tomography; single photon emission computed tomography (especially if an ictal tracer injection can be accomplished); formal neuropsychological testing; intracarotid amobarbital testing to lateralize language and memory; and, in select cases, magnetoencephalography and functional magnetic resonance imaging. If data are not concordant with regard to the likely epileptogenic and functional regions, intracranial recording with depth and/or subdural electrodes is often needed to identify these areas more definitively.

PALLIATIVE PROCEDURES

For patients who are not candidates for resective surgery, several procedures have been shown to produce worthwhile benefit in many patients, although complete seizure remission is achieved in only a few. These include disconnection procedures such as corpus callosotomy (section of the major interhemispherical commissures, often the anterior two thirds of the corpus callosum), multiple subpial transections (shallow longitudinal cuts presumed to sever cortical-cortical connections while leaving intact the descending projection fibers needed to preserve function), or insertion of the vagus nerve stimulator. The vagus nerve stimulator, which delivers controllable stimulations at programmable intervals to the left vagus nerve, produces a 50% decrease in seizure frequency among 25% to 45% of patients who undergo implantation. Its use is approved for patients 12 years of age or older with partial seizures, but younger patients and those with generalized epilepsies may respond as well or better.

COMPLEMENTARY AND ALTERNATIVE THERAPIES

Such activities as relaxation techniques, yoga, and exercise are under investigation, as are certain herbal medicines and dietary supplements. Although some of these may prove beneficial, and although relaxation and related techniques appear safe, caution must be exercised, particularly with regard to herbal preparations, because some have potentially harmful effects (including lowering the seizure threshold) or may interact with AEDs.

KEY POINTS

• Most antiepileptic drugs can be grouped into one of two classes: (1) those effective against only focal and tonic-clonic seizures (either primarily or secondarily generalized) and (2) those effective against all seizure types, including absence and myoclonic seizures.
• Within each therapeutic class, major differences have not been demonstrated in efficacy, but there are significant differences in adverse effects, time necessary to achieve a therapeutic effect, drug interactions, and cost.
• Patients whose seizures do not respond to reasonable dosages of two or three AEDs should be considered for nonmedical treatments, including resective surgery or vagus nerve stimulation.

Suggested Reading

Bromfield EB. Clinical use of anticonvulsants: a neurologist’s perspective. Harv Rev Psychiatry. 2003;11:257-268.

Bromfield EB. Epilepsy. In: Samuels MA, editor. Manual of Neurologic Therapeutics. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2004:65-75.

Duncan JS, Sander JW, Sisodiya SM, et al. Adult epilepsy. Lancet. 2006;367:1087-1100.

Spencer SS, Berg AT, Vickrey BG, et al. Predicting long-term seizure outcome after resective epilepsy surgery: the multicenter study. Neurology. 2005;65:912-918.

Wyllie E, Gupta A, Lachhwani DK, editors. The Treatment of Epilepsy: Principles and Practice, 3rd ed., Philadelphia: Lippincott Williams & Wilkins, 2005.

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