A Guide to Interventions for Pediatric Seizure Disorders

The Workforce Task Force of the American Academy of Neurology projects that the number of pediatric neurologists will be 20% below demand, at least through the year 2020.² Although it would be best for a child with epilepsy to see a pediatric neurologist, a general pediatrician, family practitioner, or adult neurologist may be required.

Traditional antiseizure medications--some of which have been in existence for almost a century--are still prescribed for children. The introduction of several new drugs over the past decade has expanded the armamentarium of possible treatments for childhood seizure disorders. When should these newer medications be administered to children? Practice parameters and reports have been put forth by expert panels on the use of these agents in children and adults.^3-8 These parameters are based on available studies, which to date are somewhat limited for children.

The first crucial step in seizure management is proper diagnosis of the seizure disorder. Conditions such as breath-holding spells, gastroesophageal reflux, syncope, movement disorders, behavioral events, conversion disorders with nonepileptic seizures, and parasomnias that mimic seizures in children must first be excluded. This requires taking a careful history of the events leading up to the episode, getting a description of the event itself, and obtaining thorough knowledge about the child's development. The second step is to determine whether the seizure was unprovoked or provoked by an immediate precipitating factor, such as fever, CNS infection, or significant head trauma.

The third step is to accurately classify the seizure type in broad terms, such as focal, focal with secondary generalization, generalized convulsive (primary generalized tonic-clonic, myoclonic, clonic, tonic, or atonic seizures), and generalized nonconvulsive (typical or atypical absence seizures). Finally, the fourth step is to determine whether the seizure pattern fits a specific epilepsy syndrome.

Some examples of common epilepsy syndromes that have onset in childhood include benign rolandic, absence and juvenile myoclonic, and Lennox-Gastaut. Factors such as age at onset, developmental level, seizure type, and EEG data aid in determining pathology. Although it is not always possible to determine the specific epilepsy syndrome, it usually is possible to categorize the disorder as focal or generalized at onset.

After the diagnosis has been determined and the family has been educated about its implications (Table 1), the next step is deciding whether medication should be prescribed. Since treatment after an initial, afebrile generalized tonic-clonic or focal seizure has not been shown to improve long-term prognosis, it is prudent to delay initiation of anticonvulsant treatment until after a second seizure occurs.³ In some instances, such as when an EEG is abnormal, treatment with an antiepileptic drug (AED) should be initiated after a first seizure if the benefits outweigh the risks.

Because infantile spasms and absence, myoclonic, and atonic seizures are recurrent, treatment typically is begun when the diagnosis is made because it is assumed that the child has experienced multiple events.³ Risk of recurrence is greatest in a child who has an abnormal EEG, underlying pathology, or evidence of an existing brain insult (such as cerebral palsy or mental retardation).

OLD VERSUS NEW

If your decision is to administer an antiseizure medication, the next step is to decide which AED to prescribe. Accurate seizure classification is critical because some AEDs are more effective against certain seizure types than others. Other factors to be considered in the choice of an AED include seizure frequency, seizure severity (physical and psychosocial consequences), side effects, titration schedule, dosing formulation, dosing frequency, drug interactions, need for therapeutic drug monitoring or other hematologic testing, comorbidities, AED prescription plan status and copay, and cost. Whenever possible, the clinician should use one drug rather than multiple drugs, choose a dosing schedule conducive to the child's lifestyle (avoid a schedule in which doses need to be given while the child is at school), and use a drug formulation that is well tolerated. Some medications come in liquid, chewable, or sprinkle form.

Should a traditional or newer AED be used? Most clinicians are more comfortable with the older AEDs.⁹ The risk/benefit ratio of any treatment must be fully evaluated by both the parent and the clinician. Because the child may need to take the medication for several years, it is important to choose an agent that is well tolerated. Factors to be considered include the patient's age, underly-ing illnesses, other long-term medications, ability to comply with the dosing schedule, and the cost.

Cost can be a major factor in treatment choice. Prices of the newer anticonvulsants are higher than those of the older ones (Tables 2 and 3). However, the newer agents typically require less laboratory monitoring, which may counterbalance cost issues. Also, the seizure control gained from using the safest and most effective medication will be associated with a reduction in the overall cost of treatment.¹⁰

On a cautionary note, however, serious adverse effects attributed to the newer drugs may not be evident until they have been more widely used, as in the case of felbamate (Felbatol, Wallace Laboratories) and its association with hepatic failure and aplastic anemia. An accompanying article (Adverse Effects of Antiepileptic Medications in Children: A Case Report and Review, page 35) details the possible adverse effects of several of the AEDs. Below, the treatment for each childhood seizure type is outlined.

GENERALIZED SEIZURES

Febrile seizures Neither continuous nor intermittent use of antiseizure medications is recommended for the treatment of febrile seizures. Educating and reassuring the patient's family is the treatment of choice. However, an American Academy of Pediatrics practice parameter, published in 1999, notes that it is acceptable to administer oral diazepam to a child to prevent seizure recurrence in instances in which the parents are experiencing severe anxiety.⁶ The recent availability of the rectal gel form of diazepam has proved effective for the treatment of seizures that do not resolve quickly and is favored by practitioners over the oral form.

Despite the advent of the newer AEDs, valproic acid is the most commonly prescribed first-line AED for a child with generalized seizures.⁹ The importance of determining the generalized nature of the child's seizure disorder is emphasized by Benbadis and colleagues,¹¹ who found that the poorly controlled idiopathic generalized seizures (absence, generalized tonic-clonic, myoclonic) of more than three quarters of their patients became well controlled once medication was changed to a broad-spectrum AED.

The broad-spectrum, or "adequate," AEDs include valproic acid, lamotrigine (Lamictal, GlaxoSmithKline), and topiramate (Topamax, Ortho-McNeil). Case reports and anecdotal evidence sug- gest that levetiracetam (Keppra, UCB Pharma) and zonisamide (Zonegran, Eisai) may be broad-spectrum. Narrow-spectrum AEDs, effective mainly against focal seizures with or without secondary generalization, include phenytoin and phenytoin sodium, carbamazepine, oxcarbazepine (Trileptal, Novartis), gabapentin (Neurontin, Pfizer), and tiagabine (Gabitril, Cephalon). These are considered inadequate because some have been shown to lack efficacy or have been associated with exacerbation of absence or juvenile myoclonic epilepsy (JME).¹¹ Ethosuximide (Zarontin, Pfizer) is only effective against absence seizures. In general, the newer medications are used as add-on medications, but as practitioners become more familiar with these drugs, they may begin to use them as monotherapy.

Absence seizures Ethosuximide, valproate sodium (Depacon, Abbott Laboratories) or valproic acid, and lamotrigine are all reasonable first-line choices for children who have newly diagnosed absence seizures.¹²

Generalized tonic-clonic seizures Medications approved for the treatment of generalized tonic-clonic seizures include valproic acid, phenytoin, and phenobarbital. Although the newer AEDs lamotrigine and topiramate have shown efficacy in populations with newly diagnosed mixed partial and generalized tonic-clonic seizures, an expert panel⁴ found insufficient data to make a specific recommendation for the use of these agents in these conditions. A pediatric neurologist should be consulted if use of a newer agent is being considered.

FOCAL SEIZURES

Carbamazepine and valproic acid are the most commonly prescribed medications for focal seizures.⁹ These AEDs were considered appropriate choices at follow-up in 85.4% of the cases in which they were used. Carbamazepine is very effective for focal seizures, especially in instances in which patients have normal brain scans and no early risk factors for epilepsy.¹³ Early risk factors include having any of the following before age 5 years: febrile seizure, CNS infection, head trauma and loss of consciousness for more than 30 minutes, and neonatal seizures. Pa- tients who have risk factors will be more resistant to first-line treatment, and a pediatric neurologist will be helpful in this situation.

Among the newer AEDs, oxcarbazepine appears to be beneficial for newly diagnosed focal or mixed seizures.⁴ It is approved as adjuvant therapy for focal and secondary generalized seizures and as monotherapy for focal seizures in children aged 4 years and older.⁸ Lamotrigine also has been approved as adjuvant therapy for focal seizures in children aged 2 years and older.⁸ Topiramate has been shown to be effective as well.

JUVENilE MYOCLONIC EPILEPSY

Valproate historically has been the initial choice for treatment of JME. JME is considered lifelong epilepsy, and the use of valproate may be limited in some patients because of potential side effects, including weight gain, bone health issues, and teratogenicity. Lamotrigine and topiramate may be useful alternatives. Lamotrigine, however, may exacerbate myoclonus. Levetiracetam and zonisamide also may be considered as potential treatments, according to case reports and anecdotal evidence.¹⁴

COMPLEX SEIZURE DISORDERS

Infantile spasms Infantile spasms is a type of epilepsy syndrome for which the standard AEDs are not effective. A pediatric neurologist should be involved with the diagnosis and care of children with this disorder. Adrenocorticotropic hormone (ACTH) is effective for short-term treatment.^7,15 Optimal ACTH dose and effect on long-term outcome are unknown. To monitor these children appropriately during treatment, primary care physicians should understand the side-effect profile of ACTH--which includes hypertension, irrtability, and infection. Vigaba- trin (Sabril, Aventis) has shown promise in the treatment of this disorder,¹⁶ but it is not approved for use in the United States.

Lennox-Gastaut syndrome The newer AEDs approved for management of Lennox-Gastaut syndrome (which involves many seizure types) are lamotrigine, to- piramate, and felbamate, but their efficacy is poor.¹⁴

SUMMARY

The diagnosis and treatment of children with epilepsy ideally should occur under the guidance of a pediatric neurologist. This is particularly true for children with epilepsy syndromes such as infantile spasms, Lennox-Gastaut syndrome, and other difficult-to-control epilepsies. If you decide that an AED is necessary, classification of the child's epilepsy by syndrome or seizure type, such as generalized or focal, is essential. The efficacy and safety of the old versus the new AEDs need to be considered to determine the best treatment for a specific patient.

Long-term follow-up of patients who are administered the newer AEDs over the next several years will provide further information about these agents' safety and efficacy in various seizure types in children. Although not addressed here, the roles of the ketogenic diet (which is not a novel idea), the vagus nerve stimulator, and neurosurgical interventions to control recalcitrant seizures need to be further elucidated. *

REFERENCES

1. Johnston MV. Seizures in childhood. In: Behram RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Philadelphia: WB Saunders Co; 2004:1993.

2. Bradley WG. Neurology in the next two decades; report of the Workforce Task Force of the American Academy of Neurology. Neurology. 2000;54:787-789.

3. Hirtz D, Berg A, Bettis D, et al. Practice parameters: treatment of the child with a first unprovoked seizure. Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2003;60:166-175.

4. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62: 1252-1260.

5. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62: 1261-1273.

6. American Academy of Pediatrics. Practice parameter: long-term treatment of the child with simple febrile seizures. Pediatrics. 1999;103:1307-1309.

7. Mackay MT, Weiss SK, Adams-Webber T, et al. Practice parameter: medical treatment of infantile spasms. Report of the American Academy of Neurology and the Child Neurology Society. Neurology. 2004;62:1668-1681.

8. Bialer M, Johannesses SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Seventh Eilat Conference (EILAT VII). Epilepsy Res. 2004;61:1-48.

9. Oka E, Murakami N, Ogino T, et al. Initiation of treatment and selection of antiepileptic drugs in childhood epilepsy. Epilepsia. 2004;45(suppl 8): 17-19.

10. Beghi E, Frigeni B, Beghi M, et al. A review of costs of managing childhood epilepsy. Pharmacoeconomics. 2005;23:27-45.

11. Benbadis SR, Tatum WO, Gieron M. Idiopathic generalized epilepsy and choice of antiepileptic drugs. Neurology. 2003;61:1793-1795.

12. Sullivan JE, Dlugos DJ. Idiopathic generalized epilepsy. Curr Treat Options Neurol. 2004;6: 231-242.

13. Dlugos DJ, Buono RJ. Predicting outcome of initial treatment with carbamazepine in childhood focal epilepsy. Pediatr Neurol. 2004;30:311-315.

14. Conry JA. Pharmacologic treatment of the catastrophic epilepsies. Epilepsia. 2005;45(suppl 5):12-16.

15. Riikonen R. Infantile spasms: therapy and outcome. J Child Neurol. 2004;19:401-404.

16. French JA. Vigabatrin. Epilepsia. 1999;40 (suppl 5):S11-S16.

17. Physicians' Desk Reference. 58th ed. Montvale, NJ: Thomson PDR; 2004.

18. Fenichel GM. Clinical Pediatric Neurology.A Signs and Symptoms Approach. Philadelphia: WB Saunders Co; 2001;29:35-45.