December 2003
Vol.10 No. 5

Editors: Dr. Sam SP Lau
Drs. Dr. Karen L Kwong, KY Wong

Anti-epileptic Drugs: Tips and Caveats

Dr. Wu Shun Ping
Department of Paediatrics, Queen Elizabeth Hospital


Introduction

Childhood epilepsy is estimated to affect about 0.5% of the young population. It is one of the most commonly encountered clinical problems in paediatrics. Paediatricians are very likely to encounter children taking anti-epileptic drugs (AED) or required to prescribe the proper AED to their patients.

How to Choose AED?

Most paediatricians agree that AED should be started for children who have two or more seizures. Despite the plethora of AED available on the market (Table 1), the old and faithful sodium valproate, carbamazepine, phenytoin and phenobarbitone are still the most commonly prescribed as they remain the most effective medications for most children with epilepsy. Although the newer AED have the benefits of fewer side effects and less drug interactions, they are only reserved as second line treatment for refractory cases in children and are given only in a minority of patients. Some newer are found to the effective in treating specific kinds of epilepsy, like vigabatrin in infantile spasms and lamotrigine in partial onset epilepsy. In case the first line AED fails to give satisfactory control, addition of a newer AED on top will improve seizure control only in a small proportion of patients.

Certain AED are contraindicated in specific types of epilepsy. For instance, carbamazepine might make typical absence epilepsy worse, while phenytoin might exacerbate myoclonic seizures. Knowing the type of seizure is therefore of paramount importance in choosing the right drug.

Sodium valproate is considered a "wide-spectrum" AED and has gained popularity in the past twenty years. There are concerned about fatal hepatitis in young children under three years old. This side effect is probably related to some obscure metabolic idiosyncrasies and is extremely uncommon. Sodium valproate has been used successfully and safely in infants with infantile spasms and benign myoclonic epilepsy of infancy, and therefore young age per se should not be a contraindication. Traditionally however paediatricians would prefer other AED to sodium valproatemin infants and very young toddlers. It may be helpful to exclude obvious mitochondrial disease by ascertaining normal serum lactate and pyruvate levels before starting it, particularly in children with developmental delay. The value of such practice, nonetheless, has not been conclusively proven.

When commencing AED it is advisable to start at small doses to avoid the dose-dependent side effects of sedation and cerebellar ataxia, which may jeopardize parental confidence and patient compliance. Drug dosage is titrated up according to clinical response and side effects. The "lowest effective dose" should be used. Children usually require a higher dose per kilogram body weight than adults due to their accelerated clearance of drugs. The maximum adult dose, however, should not be exceeded in usual circumstances (Table 1).

Side Effects of AED

The prescription of AED is a delicate art of balancing the pros and cons of these drugs. This is especially true for children with epilepsy that is difficult to control.

The dose-dependent CNS depressant side effects are common for all AED. Enquiry into sleepiness, unsteadiness, difficulty in concentration and diplpopia is an integral part of re-evaluation because these symptoms are often underreported. The depressant side effects of sodium valproate and carbamazepine usually last for several weeks after continuous use, while for phenytoin and phenobarbitone they might be more persistent. A rapid surge of circulating drug level after a morning dose might be the reason why children become very inattentive at school. Sometimes when sedation is severe, it may be helpful to switch to a sustained-release formula, which is available for sodium valproate and carbamazepine.

Apart from the dose-dependent CNS depressant effects, each AED also has its own unique side effects (Table 1). They are usually not dose-dependent. For instance sodium valproate may cause weight gain and hair loss, which are loathed by young girls. It can also cause hepatitis in an idiosyncratic manner as mentioned above.

Carbamazepine can cause a morbilliform skin rash in about 5% of recipients, and sometimes more sinister skin eruptions like erythema multiforme and Stevens-Johnson syndrome can occur. It can also cause thrombocytopenia and leucopenia, which are harbingers to drug-induced aplastic anaemia. Hence in the presence of low platelet and white cell counts, carbamazepine should be discontinued and avoided thereafter. The skin rash and bone marrow suppression usually occur in the first few months of drug usage.

Phenobarbitone is notoriously associated with hyperactivity in children, so much so that discontinuation is often necessary. In recent years phenobarbitone has somewhat fallen out of favour due to this side effect.

Owing to the possibility of hepatic and haemtological side effects, children who are commenced on treatment should have regular blood tests as a surveillance of early side effects. A reasonable approach might be to check complete blood count with differential count, liver and renal function tests at 4-6 weeks, 12 weeks and then every 6-12 months after starting treatment.

Drug Level Monitoring

Serum drug level assay is available for the first four line AED. The value of serum drug level monitoring is based on the assumption that it is proportional to the brain levels of these drugs, and hence reflects the therapeutic effect and CNS depressant side effects. It is also assumed that the metabolites of these drugs are not active, which is not true for carbamazepine (its epoxide metabolites are active).

It should be appreciated that epilepsy is a paroxysmal disorder occurring in a fluid physiological system. The milieu of a seizure is multi-faceted and as yet poorly understood. In general it would be prudent not to hastily change drug dosage basing on one breakthrough seizure or drug level result.

Drug level samples are usually taken at clinic time, and are therefore random, cross-sectional and suboptimal. The best time to take a drug level will be immediately before a dose and preferably after the patient has taken the drug long enough to achieve a steady state level. Steady state is reached in about five serum half-lives for sodium valproate, phenytoin and phenobarbitone. As for carbamazepine, however, steady state is not reached until four weeks because of the auto-induction of its own elimination.

The notion of "therapeutic range" needs clarification. "Therapeutic range" is only a crude reference and by no means implies that all patient should achieve it. A large number of children who suffer from benign childhood epilepsies are very amenable to drugs and require only a small dose of AED. On the other hand, there are patients who might require a dosage of phenytoin or sodium valproate that is higher than usual to control their refractory seizures. In the absence of significant CNS suppression, drug dosage need not be reduced even if their serum levels exceed the upper limit. Such individual variation of drug requirement should be respected.

Phenytoin and sodium valproate are highly bound to albumin in the circulation. The assay of their serum level measures the total amount of drug, not the free fraction that crosses the blood-brain barrier. Free drugs will increase when other substances compete for the same binding sites. Hence these two drugs tend to displace each other from albumin, as do other endogenous substances like bilirubin and free fatty acids. Displacement from protein binding does not usually pose a problem, but it might be important in newborns (who are prone to jaundice) and the very young children.

As a general rule, clinical assessment without drug level monitoring is adequate for patients who are under stable control. Drug level monitoring is no surrogate measure of clinical assessment. For patients taking carbamazepine and sodium valproate, regular drug level measurement is probably unnecessary. As for the ascertainment of idiosyncratic side effects listed in Table 1, drug levels have no relevance whatsoever.

Drug Interactions

The interactions between AED during polypharmacy are complicated and difficult to predict. The interference of liver metabolism and, to a lesser degree, the competition for albumin binding are the two main mechanisms of interaction.

All first line AED, except sodium valproate, are liver enzyme inducers and therefore accelerate the elimination of other AED. Sodium valproate on the other hand is an inhibitor of liver oxidation and epoxidation. It can cause accumulation of drugs like lamotrigine, carbamazepine and phenobarbitone. When combined with sodium valproate, lamotrigine should be given at one-fifth the usual dose to avoid toxicity.

Liver enzyme induction reduces the effective of other lipid-soluble drugs. Notably carbamazepine and phenytoin reduce the effectiveness of oral contraceptives, warfarin and steroids.

A number of drugs inhibit the elimination of carbamazepine. They include erythromycin, isoniazid, dextro-propoxyphene and verapamil. Their concomitant use with carbamazepine should be avoided.

Drug Discontinuation

Sudden withdrawal of the first line AED is usually avoided because of fear of precipitating status epilepticus. This is particularly true for phenobarbitone. If enteral administration of phenobarbitone has to be suspended, it will be advisable to substitute it with intravenous administration, especially if the seizure of the patient is difficult to control. Patients with benign childhood epilepsy can probably be suspended from treatment for a couple of days because of their low propensity to seizure.

Most clinicians recommend a trial of AED discontinuation after two years of freedom from seizures in children. The drugs can be tapered off over three months. Slower tapering does not have any additional benefit.

Conclusion

Most children tolerate AED treatment very well. Polypharmacy tends to complicate drug metabolism and hence might cause more side effects. Clinicians should be watchful of subtle and unreported CNS depression after treatment and adopt drug level monitoring wisely.

Recommended Reading

  1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314-9.
  2. Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med 1996;334:1583-90.
  3. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996;334:168-75.
  4. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003;349:1257-66.
  5. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology -drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349:1157-67.

The Education Bulletin of the Hong Kong Paediatric Society is created to provide members with further education in this era of information explosion. We try to make reading easy for every one. Articles should be short and concise (not more than 1500 words). We hope that every paper can be read through with ease within 10 minutes and readers should come away with at least one or two important messages or hints.

If you have any comment, suggestion or article to submit, please contact the editorial board through the publisher, Medcom Limited, Room 1310, Olympia Plaza, 255 King's Road, North Point, Hong Kong. Tel: 2578 3833, Fax: 2578 3929, E-mail: mcl@medcom.com.hk. Instruction to authors can be obtained on request.

The published materials represent the opinions of the authors and not necessarily the viewpoints of the editors, Hong Kong Paediatric Society or the publisher.