The aim of epilepsy treatment is cessation of seizures without side effects. In the course of treating the child, the family should be informed, based on their level of medical sophistication, about choices of treatment and options for dealing with the condition and its consequences. Both seizures and therapies carry risks and optimal patient care requires thoughtful balancing of these risks and benefits. To provide the best care, the physician must be aware of the available options and individualize them to the needs of the specific child (see Chapter 2).

The goals of treatment will differ considerably depending upon the severity of the epilepsy syndrome. Many childhood epilepsies are easily controlled with modest doses of medication (i.e., childhood absence epilepsy, benign epilepsy with centrotemporal spikes, and idiopathic generalized epilepsies). For these children, selecting a treatment that has no major adverse effects, yet produces seizure control in a convenient manner is a reasonable goal. Contrasted to this are children with severe forms of epilepsy, often with multiple seizure types and pharmacoresistant seizures (i.e., infantile spasms, Lennox–Gastaut syndrome and symptomatic partial onset epilepsies). For these disorders, selecting a treatment with an elevated risk–benefit ratio may be acceptable to gain improvement in seizure control. Additionally, in this group considerations of all therapeutic options should be undertaken. Finally, realistic goals for seizure control should be balanced with chronic medication side effects (especially sedation). The management of epilepsy should be conceived as a global therapeutic strategy applied to an individual child. This chapter will provide general recommendations for antiepileptic drug (AED) follow-up and withdrawal, which the physician must individualize for each child by forming a therapeutic alliance with the family.

ENSURING THAT A CHOSEN DRUG IS EFFECTIVE

Treatment should always be initiated with a single antiepileptic drug and the dose slowly increased until the seizures are controlled or until clinical toxicity occurs. Antiepileptic drugs should never be stopped abruptly unless a serious adverse event occurs (i.e., rash).

Only one in five children with epilepsy will have “smooth sailing epilepsy” (i.e., they start on an antiepileptic drug, become instantly seizure-free, and eventually come off medication and remain in remission). However, an additional 40% of children will become seizure-free with the first antiepileptic drug, after some dose adjustment to deal with subsequent seizures.¹ In general, the first antiepileptic drug will eventually be successful in controlling the seizures in 50%–70% of children. Antiepileptic drug therapy should be assessed in light of the epilepsy syndrome and a risk-to-benefit profile established when considering the various antiepileptic drugs. Initiation of antiepileptic therapy should be done with a realization that about half of the time the initial antiepileptic drug will be changed. As a result, compatibility of the initial antiepileptic drug with future antiepileptic drugs should be considered when initial therapy is begun. If monotherapy fails, and a combination of antiepileptic drugs is used, then drugs effective for the particular seizure type with low risk of pharmacokinetic interaction and differing mechanisms of actions are preferred.

FREQUENCY OF FOLLOW-UP

There are no studies that address the optimal approach to outpatient care for children being treated with antiepileptic drug. Physician or epilepsy nurse contacts need to be frequent enough to maximize drug efficacy, monitor side effects, and screen for psychosocial or other health issues. How frequently this occurs will vary from child to child. It is realistic to evaluate children who are doing well 4–6 weeks after beginning treatment, at 3 months, and then every 6 months thereafter. The initial visit is particularly important to assess behavioral and cognitive side effects of antiepileptic drugs.

Medication Adherence

Medication adherence should be assessed at each visit. Using a 7-day pill dispenser, strategies for dealing with missed doses, and physician interest in the number of misses doses helps improve adherence with an antiepileptic drug treatment plan. The family should have a detailed plan for what to do if a medication dose is missed and for a seizure emergency.

When seizures continue at the maximally tolerated dosage, the most common strategy is to substitute a second drug for the first, given as monotherapy.^2,3 In practice, to minimize the risk of withdrawal seizures, it is preferable to avoid abrupt discontinuation of the preexisting antiepileptic drug when switching to an alternative medication. A therapeutic strategy that is an intermediate step between alternative monotherapy and combination therapy involves adding a second drug, stabilizing the patient for a period sufficient to access the response to combination therapy, and then proceeding with the gradual removal of the initial drug, if a good response has been achieved. This transition phase allows the effect of the combination of the two drugs to be tested. If the child needs the drug combination to remain seizure-free, this will become apparent and the withdrawal procedure can be rapidly reversed. Historically, this procedure had the major drawback of possibly exposing the patient to adverse drug interactions and to side effects of polytherapy. However, the newer antiepileptic drugs have fewer interactions and are better tolerated, potentially making this option more attractive.

Choosing an alternative monotherapy or adding a second drug is a matter of personal preference, as no sound evidence is available to indicate that one choice is superior to the other.^4,5 The inability to document improved efficacy with two drugs, combined with the potential for increased adverse events and cost, is probably why surveyed experts suggest a second trial of monotherapy prior to polytherapy.² Combination therapy should be reserved for patients who are refractory to two or more sequential monotherapy trials.

Clinical evidence only indicates a few drug combinations that are more advantageous than others. The best examples of useful antiepileptic drug combinations are valproate and ethosuximide in the management of refractory absence seizures and valproate–lamotrigine in refractory partial onset seizures.

Under usual circumstances, the assessment of therapeutic response is based on observation of seizures. Parents should carefully record all seizures in a diary, utilizing simple codes that allow differentiation by seizure type. In addition to recording seizure type and the date on which it occurs, the length of the seizure, time of day when it occurred, and days when medication doses were missed should also be recorded.

Baseline seizure frequency needs to be considered: if at baseline the child is having one seizure every 2 or 3 weeks, it may take up to 2 months, three to four times the baseline interval, to determine with confidence whether a change in drug therapy led to seizure freedom.

Antiepileptic drug therapy is typically aimed at suppressing the clinical manifestation of seizures whereas normalization of the EEG is typically not a primary or attainable goal. However, in some epilepsy syndromes, suppression of epileptiform EEG abnormalities is a justifiable therapeutic goal. This occurs when there is a close correlation between clinical seizures and EEG paroxysms, and seizures are not easily quantifiable clinically as in childhood absence epilepsy and photosensitive epilepsies. In infants and children with severe epileptiform abnormalities coexisting with encephalopathy, the extent of the EEG-related dysfunction should be determined and vigorous treatment may abate its effect. Examples include infantile spasms and Landau–Kleffner syndrome or CSWS (continuous spikes in slow-wave sleep). Monitoring EEG responsiveness in these patients can be useful in optimizing therapy.

A CONCEPTUAL FRAMEWORK

Rarely do clinical trials address some of the critical decisions that are essential to patient management: when to stop using a particular antiepileptic drug or when to switch to another medication. However, a basic conceptual framework that is evidence-based can help in deciding when to stop and when to switch antiepileptic drugs for an individual child. This conceptual framework has changed in the last two decades because of an increased number of available treatment options and a better understanding of epilepsy response to antiepileptic drug therapy.

Historically, clinicians would titrate a single drug to seizure control or toxicity. Evidence from recent studies can be used to support a new conceptual framework for pursuing antiepileptic drug polytherapy (Fig. 48–1). The first principle is that most children who are responders to a given antiepileptic drug respond to treatment early. Second, most responders do so at low to moderate doses. Data for antiepileptic drugs suggest a steep response curve, so that very high doses only account for another 5%–10% of responders. Keeping these two principles in mind, it is probably unnecessary to push a drug to maximum doses before deciding if the patient will likely respond. However, if the child shows a partial response to a low to moderate does, this identifies a drug that should be increased to either seizure control or toxicity. Finally, initiate therapy with an antiepileptic drug that has few pharmacokinetic or pharmacodynamic interactions and add a second antiepileptic drug if it shares the same properties. Keeping these principles in mind allows the clinician to establish a rational methodologic approach to antiepileptic drug management.

First, select an appropriate antiepileptic drug based on the epilepsy syndrome and individual patient characteristics, targeting a midrange dose. Next, critically reevaluate the antiepileptic drug response soon after each change, typically in 4–6 weeks. If the child has shown a greater than 50% reduction in seizure frequency, but is not seizure-free, increase the drug dose until side effects occur or there is seizure freedom. However, if there is no significant response, select a new antiepileptic drug and stop the prior one. This strategy allows the most efficacious and best-tolerated medication selection and an efficient use of time to determine the best combination drug therapy. This strategy is employed after critical evaluation in a specialized pediatric epilepsy monitoring unit, with consideration of all nonpharmacologic and pharmacologic treatment options for the given epilepsy syndrome and etiology (Fig. 48–2).^2,6 Using this conceptual framework will allow a rational approach to polytherapy for the child with seizures that are difficult to control.

WHEN SEIZURE CONTROL IS INCOMPLETE AT MAXIMUM DOSE

In patients whose seizures cannot be controlled completely by anticonvulsant medication at maximally tolerated dosage, it is a secondary aim to suppress or reduce the frequency of those seizures that have the worst impact on the patient’s quality of life. For example, control of drop attacks in patients with Lennox–Gastaut syndrome may produce far greater benefits than suppression of associated atypical absence seizures. Treatment that prevents secondary generalization of seizures would be expected to have a major impact on the quality of life of a patient with simple partial seizures.

Although achieving seizure control is usually the most important objective of medical management, seizures are not the only cause for concern in patients with epilepsy. Associated neurologic, intellectual, psychological, and social handicaps must also be addressed (Table 48–1). Whenever complete seizure freedom proves to be a nonrealistic goal, optimal treatment results from a compromise between the desire to minimize seizure frequency and the need to maintain side effects within acceptable limits.

ADOLESCENCE

Specific issues unique to adolescents must be addressed to allow the teenager to pass successfully from childhood to adulthood. The concerns, which need to be addressed, as voiced by teenagers, include choices of further education and career, the possibility and risk of withdrawing from anticonvulsants, driving regulations, the inheritance of epilepsy, leisure activities, alcohol use, pregnancy, and contraception.⁷ The pediatric neurologist needs to prepare children with persistent epilepsy for transfer to adult epilepsy services.

COMORBIDITIES

The majority of children with epilepsy have other neurologic comorbidities at the time of diagnosis. These comorbidities may have a greater impact on a child’s life than do seizures.⁸ The initial and follow-up assessments for epilepsy should include thorough questioning about cognitive and behavioral problems and sleep difficulties.⁹ Screening questionnaires can be very revealing.

ADVERSE DRUG REACTIONS

Prescription of antiepileptic medication entails a significant risk of side effects. Choice of drug and dosage needs to be tailored to individual needs. In many patients with newly diagnosed epilepsy, it is realistic to expect seizure control at dosages that produce no toxicity. For a given seizure type or epilepsy syndrome, there are often two or more antiepileptic drugs with relatively similar efficacy; thus the choice of drug may be largely determined by the side effect profile.

It is critical that the child being treated for epilepsy be monitored carefully, not only for seizure activity but also for potential adverse events. It is important to inform the family about side effects that may be anticipated and any action that may need to be taken, particularly with respect to early signs of serious toxicity. While laboratory safety monitoring may be recommended for certain drugs (felbamate, most notably) for detection of serious adverse effects, it is much more important to alert the patient about the need to recognize immediately any warning symptoms.¹⁰ For example, bleeding, bruising, and infections may be manifestations of a blood dyscrasia, whereas vomiting, anorexia, sedation, and increased seizure frequency in a patient treated with valproate should raise the possibility of liver toxicity. It is especially important to appreciate age-specific organ toxicities.

Acute idiosyncratic reactions are rare, unpredictable, and necessitate immediate withdrawal of the causative drug. In children, allergic reactions manifested by rash, with or without multiorgan involvement or fever, constitute the most common idiosyncratic reaction. These occur more commonly in patients exposed to carbamazepine, phenytoin, phenobarbital, or lamotrigine. Patients should be counseled with regard to the timing of occurrence (typically the first 4 weeks) of this reaction and have a plan for contacting the prescribing physician.

Two studies address the lack of value of routine blood work for assessment of toxicity in asymptomatic children with epilepsy taking an antiepileptic drug. Based on this evidence, in 1989, the Canadian Associates for Child Neurology developed a consensus statement that concluded that there was no proven benefit in screening asymptomatic children, but rather that parents should be instructed to report early symptoms or signs of a possible drug reaction, which should then be investigated.¹¹ Chronic toxicity can affect any organ system and should be monitored for at regular follow-up visits.

TERATOGENICITY

Teratogenicity is a special issue that must be reviewed in all adolescents of childbearing age. Different antiepileptic drugs carry differing risks of teratogenicity,¹² and increased drug burden appears to elevate this risk. Review of the antiepileptic drug, its risk of teratogenicity, and the need for ongoing antiepileptic drug therapy should be discussed with every adolescent female with epilepsy, and changes made in their drug therapy, if appropriate.

ANTIEPILEPTIC DRUG-RELATED SEIZURE EXACERBATION