The treatment of seizure disorders has advanced considerably during the past decade. Newer surgical techniques, vagal nerve stimulation, the rediscovery of diet therapy, and the development of drugs with a variety of mechanisms of action have greatly enhanced the ability to manage seizure disorders in both children and adults. The mainstay of treatment remains pharmacotherapy.
The general pediatrician is often the first to evaluate a child with a seizure. If prophylactic drug treatment is indicated, the pediatrician must be able to choose the most appropriate drug for the seizure type and monitor its effectiveness and side effects to ensure maximum benefits and patient compliance. The availability of so many anticonvulsant drugs makes the selection more difficult (Table 1). Understanding the indications, pharmacology, and adverse side effects will make this decision easier.
In the best of all worlds, seizures would be eliminated without adverse effects significant enough to impair quality of life. No currently available drug can meet these stringent criteria. Instead, a balance must be struck between seizure control and adverse effects. Therefore, the primary goal of therapy is to maximize seizure control and rninimize adverse effects.
Phenobarbital has been a mainstay of anticonvulsant treatment for children since its discovery in the late 1920s. By decreasing the activity of the cerebral cortex, phenobarbital can control both generalized tonic-clonic and partial seizures, but is not generally useful in the control of absence seizures.1 It is a second-line therapy for status epilepticus, behind benzodiazepines and phenytoin. The loading dose of phenobarbital for status is 15 to 20 mg/kg given intravenously. The intravenous push rate should not exceed 1 mg/kg/min due to the incidence of hypotension and respiratory depression. For oral administration, phenobarbital should be dosed at 3 to 5 mg/kg in 1 to 2 divided doses per day. Phenobarbital is available as tablets, elixir, and injectable liquid; however, some children may reject the elixir due to a bitter taste. Seizure control is frequently obtained as the serum phenobarbital level rises into the therapeutic range of 15 to 40 μg /ml. Phenobarbital serum levels are linearly related to the dose of the drug.
Toxic side effects, such as altered sleep, fussiness, irritability, recalcitrance, or hyperactivity. are often seen at serum levels greater than 60 µg/ ml. But, impaired cognitive effects, including decreased attention, problem-solving, and visuomotor abilities, have been noted in both children and adults at lower concentrations. Phenobarbital is metabolized in the liver by cytochrome P450 enzymes. Its induction of these enzymes may increase the clearance of other drugs metabolized by the same pathway.
Drug Choices for the Treatment of Epileptic Seizures
Primidone is actually three drugs in one - the parent compound and its two active metabolites, phenobarbital and phenylethylmalonamide. Thus, its mechanism of action is similar to that of phenobarbital. It too is used to treat generalized and partial motor seizures.2 Oral dosing is begun at 50 mg every 24 hours or 2 to 4 mg/kg/d and gradually increased to 150 to 500 mg every 24 hours. Administration is divided in 3 doses to achieve a serum level between 5 and 12 µg/ ml, as well as a phenobarbital level of 15 to 40 µg /ml. Toxic effects are similar to those of phenobarbital.
Ethosuximide has been used almost exclusively for the treatment of absence seizures because it depresses the paroxysmal three per second spike and wave electroencephalogram (EEG) activity of these seizures.3 Given only by the oral route, ethosuximide has a long half-life and is suitable for once a day dosing at 10 mg/kg/d. However, ethosuximide is usually given in 2 divided doses to minimize gastrointestinal upset. Rarely, idiosyncratic blood dyscrasias have been reported. Fatigue, anorexia, abdominal discomfort, nightmares, and dizziness have also been observed. Emosuximide has little interaction with other drugs.
Carbamazepine is now the principal antiepileptic medication for children and adults with generalized and partial seizures. The drug should not be used for patients with absence seizures or juvenile myoclonic epilepsy because it may worsen seizure frequency and severity. Carbamazepine, and its active metabolite carbamazepine epoxide, appears to block voltagedependent sodium channels.4 The initial dose for carbamazepine in children is 5 mg/kg/d, gradually increasing to a maintenance of 20 to 40 mg/kg/d. Carbamazepine induces its own metabolism, decreasing its half-life over time. Maximal autoinduction, which occurs at approximately 28 days after first adjninistration, often requires a dosage increase. Carbamazepine interacts with several other drugs, especially erythromycin. The latter, when prescribed to a patient who is already taking carbamazepine, will significantly elevate the anticonvulsant drug's plasma concentration. Carbamazepine is available in tablets, chewable tablets, and liquid formulations. Two long-acting formulations of carbamazepine are now available. These are Tegretol XR (Novartis, Summit, NJ), which incorporates carbamazepine into a slow-release delivery system, and Carbatrol (Shire Richwood, Inc., Florence, KY), a capsule that contains entericcoated time-released beads.
Dizziness, diplopia, agitation, and transient benign leukopenia are common side effects. The leukopenia usually corrects itself within the first 4 weeks of therapy.5 The other side effects, including a less common syndrome of inappropriate antidiuretic hormone secretion, are concentration related and respond to dosage alterations. The more serious idiosyncratic complications of aplastic anemia or erythema multiforme may occur on rare occasions and require withdrawal of the drug.
Phenytoin is probably the most widely studied anticonvulsant because it decreases seizure activity without significant central nervous system (CNS) depression. Phenytoin does this by influencing numerous CNS biochemical and physiologic systems, including sodium channel regulation and the ability to limit the seizure discharge from a seizure focus.6 It is a drug of choice for simple and complex partial seizures and generalized tonic-clonic seizures. Phenytoin can be useful in neonatal seizures and in the acute treatment of status epilepticus if given by intravenous formulation. A variety of formulations are suitable for pediatric adjninistration, including suspension, chewable tablets, and capsules. A dose of 3 to 10 mg/kg, given in 1 to 3 divided doses, is appropriate for beginning pediatric administration. Serum levels in the range of 10 to 20 ^g/ ml are considered target concentrations, although children require higher levels to maintain seizure control. Saturation of the liver enzymes that metabolize phenytoin may occur in the therapeutic ranges. Thus, a small change in dose may produce significant increases in serum concentrations. Nausea, vomiting, and ataxia are toxic effects related to the serum level. Gingival hyperplasia, hirsutism, and acneiform eruptions appear to be non-dose-dependent.
Fosphenytoin sodium is a prodrug of phenytoin available in injectable form. Its indications are the same, but it has distinct advantages over phenytoin. It may be administered intravenously or intramuscularly and has fewer administration adverse effects. However, it is significantly more expensive than standard phenytoin injectable therapy.7
In clinical use for more than 30 years, valproic acid has established itself as first-line therapy for partial, generalized tonic-clonic, and absence seizures.8 Although no one mechanism has been found to explain the wide spectrum of activity of valproic acid, a leading hypothesis is that it increases 7-aminobutyric acid (GABA) levels. Valproic acid is manufactured as an oral liquid and as an injectable liquid for intravenous use, immediate-release and delayed-release tablets, and as sprinkles. Although the effective maximum dose is uncertain, a starting dose of 10 to 15 mg/kg may be titrated to a stated 60mg/kg maximum dose during 1- to 2- week intervals. Gastrointestinal upset is common at the beginning of therapy, but is less likely with enteric-coated forms. Tremors and thrombocytopenia appear to be dose-related adverse effects. Excessive weight gain is not uncommon and may require discontinuation of the drug. Pancreatitis is a rare complication. Fatal hepatotoxicity has been reported with valproic acid. This appears to be idiosyncratic and more likely in young children who are taking multiple anticonvulsant medications. The periodic evaluation of hepatic enzymes for early detection of liver failure due to valproic acid is still a matter of controversy.9
Benzodiazepines are commonly used to treat status epilepticus and occasionally used as adjunctive therapy for absence seizures and minor motor seizures. Lorazepam or diazepam may be given intramuscularly, intravenously, or rectally. The Food and Drug Administration (FDA) has recently approved diazepam rectal gel for the treatment of acute repetitive seizures. This formulation is designed for caregivers to begin control of status epilepticus in patients with frequent seizures prior to emergency medical care.10
Felbamate was approved in 1993 for adjunctive or monotherapy treatment of adults with partial seizures, with or without secondary generalization. It is also approved for use in pediatrie patients with Lennox-Gastaut syndrome.11 Felbamate inhibits the metabolism of phenytoin, valproic acid, and the active metabolite of carbamazepine. A 20% to 30% reduction in dosages of concurrent antiepileptic medication is usually required at the initiation of felbamate therapy
Initial dosing for pediatric patients should begin at 15 mg/kg/d in 3 to 4 divided doses. This may be increased weekly by 15 mg/kg/d to 45 mg/kg/d, with a maximum dose of 3.6 g/d. It is well absorbed orally and is currently available in 400- and 600-mg tablets plus a 125-mg/ml suspension.
The most common adverse effects are anorexia, insomnia, nausea, vomiting, and ataxia. All have been experienced more often in patients who are taking multiple antiepileptic medications. The most serious adverse effects reported with felbamate are aplastic anemia or hepatic failure. In August 1994, the FDA and the manufacturer recommended the use of felbamate only for patients who have substantially benefited from it or for patients with seizure disorders refractory to standard therapy.
Lamotrigine has previously been used to treat adults with partial seizure disorders, but was recently approved for pediatric patients with Lennox-Gastaut syndrome. Approval from the FDA for partial seizure disorders in pediatrics is expected in 1999. Lamotrigine appears to inhibit the release of excitatory neurotransmitters, particularly glutamate. In addition, lamotrigine may block sodium channels, thus suggesting it will have efficacy against a broad range of seizure types.12 Established pediatric dosage guidelines are to use a starting dose between 0.2 and 2 mg/kg/d. This may be increased to a maximum of 5 to 15 mg/kg/d, depending on concurrent antiepileptic drug (AED) administration in the patient. A somewhat complicated dosing schedule for children is based on concurrent AED therapy. Valproate decreases the clearance of lamotrigine significantly. Many of the other liver enzyme-inducing AEDs (such as phenytoin, phénobarbital, and carbamazepine) also decrease the clearance of lamotrigine. A significant rash requires discontinuation of lamotrigine in 1 in 1,000 adults and 1 in 50 to 100 children. The rash may be consistent with Stevens-Johnson syndrome and may potentially be life threatening. The rash is more common in children, especially when the dose is increased rapidly and given concurrently with valproic acid. This is because valproic acid increases the half-life of lamotrigine to approximately 6 days. The most common adverse effect is drowsiness.
Gabapentin is a new anticonvulsant licensed in 1994 for the treatment of partial seizures, with or without generalization, in adults. It is structurally similar to GABA, but the complete mechanism of action is unknown.13 Currently, it is not approved in children and available only as 100-, 300-, and 400-mg tablets. However, pediatric trials have recently been concluded, and pediatric approval is expected by the FDA in 1999, primarily for partial seizures. Gabapentin's main advantage over other anticonvulsants is that it is not protein bound and does not induce liver enzymes, thereby reducing the potential for drug-drug interactions. However, gabapentin does have a short half-life of 5 to 7 hours, so frequent dosing is required. Adverse CNS effects, including somnolence, dizziness, ataxia, and fatigue, are usually mild and transient.
Pharmacokinetics of Antiepileptic Drugs
Vigabatrin is another anticonvulsant with structural similarities to GABA. Because of visual field defects, vigabatrin was denied approval by the FDA and currently is not available in the United States. It is possible that vigabatrin may be resubmitted to the FDA under orphan drug status for the treatment of infantile spasms. Vigabatrin inhibits GABA transaminase, the enzyme principally responsible for termination of the activity of GABA. It thereby increases the level of GABA in the CNS. Initial studies performed in children included a single center, single-blinded add-on project by Dulac et al.14 This involved 66 subjects having symptomatic partial epilepsy, symptomatic generalized epilepsy, Lennox-Gastaut syndrome, cryptogenic partial epilepsy, or nonprogressive myoclonic epilepsy. During the first 6 months, 46% of the subjects had a greater than 50% reduction in seizure frequency, whereas 15% experienced an increase in seizure activity. Chiron et al.15 have studied the use of vigabatrin in children with infantile spasms. Seventy children between 2 months and 13 years old were enrolled in this add-on open trial. The most impressive results were seen in children with infantile spasms due to tuberous sclerosis: all maintained complete seizure control for a long-term follow-up period of 8 to 33 months. The recommended starting dose for children is 40 mg/kg/d, increasing to 80 to 100 mg/kg/d depending on response. For infantile spasms, a dose greater than 100 mg/kg/d may be required. The most common adverse effects are CNS related, including drowsiness and fatigue. The drug has little interaction with other medications.
Topiramate was licensed by the FDA in December 1996 as a unique new addition to currently available anticonvulsants. Although its exact mechanism is not known, topiramate appears to affect sodium channels, GABA receptors, and glutamate receptors. It is thus effective against a broad spectrum of seizure types. There have been only a small number of clinical trials in children. Espe-Lipo et al.16 reported that 80% of their subjects had a 50% reduction in seizure frequency. In this open-label trial, subjects had complex partial seizures, partial seizures, or the Lennox-Gastaut syndrome. Initial dosages in adults begin at 50 mg/d as adjunctive therapy, increasing to 400 mg/d in divided doses. Pediatric dosing is 3 to 9 mg/kg/d in divided doses, beginning at 1 mg/kg/d. The drug is available in tablets and sprinkles.
Topiramate appears to have few drug interactions, but substances that induce liver enzymes may increase its clearance. Adverse effects in children were mild to moderate CNS-related symptoms, including tiredness, irritability, somnolence, and fatigue. At high doses, cognitive effects may become apparent. Renal calculi are a rare complication, and the drug should be used with caution in children who are taking acetazolamide or who are on a ketogenic diet.
Tiagabine is approved for the treatment of complex partial seizures in adults. It blocks the reuptake of GABA into presynaptic neurons and glial cells, thus increasing the level of GABA in the CNS. In adult studies, tiagabine has produced significant decreases in complex partial seizure frequency when used as adjunctive therapy.17 Pediatric success with tiagabine has been anecdotally reported for infantile spasms and the Lennox-Gastaut syndrome. Recently completed pediatric clinical trials have demonstrated success in the treatment of complex partial seizures.1819 Although tiagabine is not yet approved in pediatrics, available pharmacokinetic information suggests a starting dose of 0.1 mg/kg/d with a maintenance dose of 1 to 1.5 mg/kg/d. Because tiagabine is not approved for patients younger than 18 years of age, pediatric formulations are not currently available. The most common adverse effects in adult studies are dose related and affect the CNS. These include dizziness, tremor, abnormal thinking, and depressed mood. The drug has little interaction with other medications.
Pharmacologic Properties of Antiepileptic Drugs
Comparative Costs for Antiepileptic Medications
Initiation of therapy should always be undertaken with a single drug selected specifically for the diagnosed seizure type.20 It is preferable to start with one that is indicated for first-line therapy (Table 1). Monotherapy is generally considered the best approach, as polytherapy does not appear to provide additional efficacy in most cases but does increase the incidence of adverse effects. However, with the advent of newer drugs with different mechanisms of action, it may be possible to design polytherapy that would provide complementary effects.
The dosage of the selected drug should be increased gradually to allow time for tolerance to adverse effects to develop. The dose should be pushed until either seizure control is obtained or intolerable adverse effects appear. AED serum concentrations are useful guides for detennining drug dosage, but are not the primary measure of efficacy. Guidelines for indications and frequency of therapeutic monitoring have been published.21 One should routinely measure AED serum concentrations after initiating therapy and after changing the regimen to ensure adequacy of dosing. Serum concentrations should also be measured when there are signs of unexpected toxicity, to verify compliance, when there is suspicion of drug interactions, or when there is a change in hepatic or renal function. The optimal use of AEDs must take into account the pharmacologic and pharmacokinetic properties of the drugs, especially in relation to the population in which they will be used. Tables 2 and 3 provide this information for both adults and children. Another consideration, especially for young children, is the availability of appropriate dosage forms. Many, but not all, AEDs have suitable formulations (Table 3).
Once the proper diagnosis is made and the appropriate drug has been chosen, the most common cause of treatment failure is noncompliance.22 It is difficult to guarantee compliance, especially with chronic conditions. Diligence must be exercised to ensure that as few doses as possible are missed. This requires education and encouragement for both patient and caregiver. If a child fails an adequate trial of an AED, a second front-line drug should be tried and the first drug should be tapered and discontinued. One should ensure that the type of seizure or epilepsy has been properly diagnosed. A neurologic consultation should be obtained if the diagnosis is unclear or if there is treatment failure.
Costs are always a concern, particularly with the advent of managed care. Table 4 lists costs for comparative purposes. The average wholesale price is an arbitrary figure and represents what a manufacturer considers the average price charged to wholesalers. In addition, costs to the patient are increasingly often regulated by thirdparty payers.
Most cases of epilepsy can be managed effectively by primary care pediatricians. Currently approximately 70% of patients can achieve acceptable control of their seizures with traditional AEDs. Although not yet proven, it is anticipated that the addition of newer AEDs may substantially increase this percentage while decreasing the number of adverse effects.
1. Painter MJ, Gavs LM. Phénobarbital: clinical use. In: Levy RH, ed. Antiepileptic Drugs, 4th ed. New York: Raven; 1995:401^07.
2. Smith DB, Detoledo J. Primidone: clinical use. In: Levy RH, ed. Antiepileptic Drugs, 4th ed. New York: Raven; 1995:477-485.
3. Sherwin AL. Ethosuximide: clinical use. In: Levy RH, ed. Antiepileptic Drugs, 4th ed. New York: Raven; 1995: 667-673.
4. Loiseau P, Duche' B. Carbamazepine: clinical use. Ln: Levy RH, ed. Antiepileptic Drugs, 4th ed. New York: Raven; 1995:555-563.
5. Evans OB, Gay H, Swisher A, Parks BR. Hematologic monitoring in children with epilepsy treated with carbamazepine. / CAtW Neurol. 1989;4:286-290.
6. Wilder BJ. Phenytoin: clinical use. In: Levy RH, ed. Antiepileptic Drugs, 4th ed. New York: Raven; 1995: 339-344.
7. Morton LD. Clinical experience with fosphenytoin in children. / CAfW Neurol. 1998;13(suppl 1):S15-18.
8. Bourgeois BF. Valproic acid: clinical use. In: Levy RH, ed. Antiepileptic Drugs, 4th ed. New York: Raven; 1995: 633-639.
9. Penry JK, Dean JC. Valproate. In: Dodson WE, Pellock JM, eds. Pediatric Epilepsy Diagnosis and Therapy. New York: Demos; 1993:315-324.
10. Kriel Rl, Cloyd JC, Hadsall RS, et al. Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis. Pediatr Neurol. 1991;7:13-17.
11. Felbamate study group in Lennox-Gastaut syndrome. Efficacy in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med. 1993;328: 29-33.
12. Besag FMC, Wallace SJ, Dulac O, Aving J, Spencer SC, Hosking G. Lamotrigine for the treatment of epilepsy in childhood. / Pediatrics. 1995;127:991-997.
13. Khaurana DS, Rivello J, Helmers S, Holmes G, Anderson J, Mikati MA. Efficacy of gabapentin therapy in children with refractory partial seizures. / Pediatrics. 1996;128: 829-833.
14. Dulac O, Chiron C, Lima D, et al. Vigabatrin in childhood epilepsy. /CAiW Neurol. 1991;6:30-37.
15. Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. / CAtW Neurol. 1991;6:52-59.
16. Espe-Lipo J, Ritter FJ, Frost MD, Speigel RH, Reife RA. Topiramate in childhood epilepsy: titration, adverse effects, and efficacy in multiple seizure types. Epilepsia. 1995;36(suppl 4):56. Abstract.
17. Uthman BM, Rowan AJ, Ahmann PA, et al. Tiagabine for complex partial seizures: a randomized, add-on doseresponse trial. ArcA Neurol. 1998;55:56-62.
18. Boellner S, McCarty J, Mercante D, Sommerville K. Pilot study of tiagabine in children with partial seizures. Epilepsia. 1996;37(suppl 4):S92.
19. Boellner SW, Deaton R, Sommerville KW. Long term treatment of partial seizures with tiagabine in children. Epilepsia. 1997;38(suppl 8):S208.
20. Anonymous. Drugs for epilepsy. Med Lett Drugs Ther. 1989;31:1-4.
21. Commission on Antiepileptic Drugs, International League Against Epilepsy. Guidelines for therapeutic monitoring on antiepileptic drugs. Epilepsia. 1993;34:585-587.
22. Peterson GM, McLean S, Milligan KS. A randomized trial of strategies to improve patient compliance with anticonvulsant therapy. Epilepsia. 1984;25:412-417.
Drug Choices for the Treatment of Epileptic Seizures
Pharmacokinetics of Antiepileptic Drugs
Pharmacologic Properties of Antiepileptic Drugs
Comparative Costs for Antiepileptic Medications