childhood
pharmacological considerations
B.F.D. Bourgeois The Cleveland Clinic Foundation
Introduction Over .the past two decades, progress in the treatment of childhood epilepsy has not been characterized by any major breakthroughs. However, improvements occurred in several areas, including the development of new drugs, a better understanding of pharmacokinetics, the improved use of drug level monitoring, simplification of therapy geared towards an optimal efficacyhoxicity ratio, better awareness of specific indications and, last but not least, a better understanding of the role of epilepsy surgery in the pediatric age range. No major antiepileptic drug was released for many years following the introduction of valproic acid, but several promising drugs have been very recently released or are about to be marketed in certain countries, such as vigabatrin, lamotrigine and felbamate. This is the result of widespread systematic efforts. If approved, felbamate will be the first antiepileptic drug to be released in the U S . with an indication that already includes childhood epilepsy. Studies of age-related pharmacokinetics, together with more systematic and more judicious use of drug levels, have reduced the inaccuracies in the dosage. The general philosophy of seizure therapy has shifted towards a
Address: B.F.D. Bourgeois Department of Neurology - S 53 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195-5221 U.S.A.
concept of quality of life rather than an “all-out war” against seizures. Thus, for example, chronic prophylactic therapy of simple febrile seizures has been virtually abandoned, and the idea of withholding treatment in mild or benign forms of epilepsy has gained more respectability. There is little doubt that, on the average, children with refractory epilepsies are now treated with a smaller number of drugs than 20 years ago, with a concomitant reduction in sedativekognitive effects, and without a loss in seizure control. One of the most recent developments in pediatric epilepsy has been the application of the knowledge acquired in adults in the area of pre-surgical seizure monitoring and epilepsy surgery. The result has been, in particular, a lowering of the average age at which patients with partial epilepsy undergo excisional surgery. The increased awareness of epilepsy surgery as an alternative has increased the necessity to better define medically intractable epilepsy and to accelerate the process of documenting medical intractability. In the present review, the issues that will be discussed are the relative efficacy and safety of the available antiepileptic drugs and the rationale for considering or avoiding drug combinations.
Efficacy and safety of available antiepilepticdrugs Failure of antiepileptic therapy can consist of incomplete seizure control without side effects, complete seizure control possible only with side effects, or incomplete seizure control with persistent side effect. Antiepileptic drugs do not differ much in terms of efficacy, but they do have different types and degrees of toxicity. Often, efficacy and safety are analyzed separately, but no therapy can be assessed adequately, unless the risks and the benefits are always evaluated together. This is best expressed as a therapeutic index (TI) or protective index, a ratio between
23
Bourgeois a quantative assessment of seizure reduction and a quantative assessment of undesirable side effects. As we will see, there is no universal TI for any drug that would apply to all patients. The TI of a drug may be different in every patient and, in the same patient. it may vary with changes in dosage or with time. In everyday practice. the TI cannot be expressed in units or precise numbers, but at least four different TI’S can be distinguished for practical purposes: 1. The TI can be “neutral”, which means that there is no therapeutic effect and no evidence of toxicity: 2. The TI can be “1” when there is a therapeutic response with corresponding “acceptable” toxicity; 3. The TI can be > 1, indicating that there is a good response with little or no toxicity; 4. All too often, the TI is < 1, when objective assessment reveals that the patient has actually not experienced any decrease in seizure frequency, but clearly experiences toxicity, or when toxicity is greater than efficacy. The reason why a TI
pharmacological considerations
B.F.D. Bourgeois The Cleveland Clinic Foundation
Introduction Over .the past two decades, progress in the treatment of childhood epilepsy has not been characterized by any major breakthroughs. However, improvements occurred in several areas, including the development of new drugs, a better understanding of pharmacokinetics, the improved use of drug level monitoring, simplification of therapy geared towards an optimal efficacyhoxicity ratio, better awareness of specific indications and, last but not least, a better understanding of the role of epilepsy surgery in the pediatric age range. No major antiepileptic drug was released for many years following the introduction of valproic acid, but several promising drugs have been very recently released or are about to be marketed in certain countries, such as vigabatrin, lamotrigine and felbamate. This is the result of widespread systematic efforts. If approved, felbamate will be the first antiepileptic drug to be released in the U S . with an indication that already includes childhood epilepsy. Studies of age-related pharmacokinetics, together with more systematic and more judicious use of drug levels, have reduced the inaccuracies in the dosage. The general philosophy of seizure therapy has shifted towards a
Address: B.F.D. Bourgeois Department of Neurology - S 53 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195-5221 U.S.A.
concept of quality of life rather than an “all-out war” against seizures. Thus, for example, chronic prophylactic therapy of simple febrile seizures has been virtually abandoned, and the idea of withholding treatment in mild or benign forms of epilepsy has gained more respectability. There is little doubt that, on the average, children with refractory epilepsies are now treated with a smaller number of drugs than 20 years ago, with a concomitant reduction in sedativekognitive effects, and without a loss in seizure control. One of the most recent developments in pediatric epilepsy has been the application of the knowledge acquired in adults in the area of pre-surgical seizure monitoring and epilepsy surgery. The result has been, in particular, a lowering of the average age at which patients with partial epilepsy undergo excisional surgery. The increased awareness of epilepsy surgery as an alternative has increased the necessity to better define medically intractable epilepsy and to accelerate the process of documenting medical intractability. In the present review, the issues that will be discussed are the relative efficacy and safety of the available antiepileptic drugs and the rationale for considering or avoiding drug combinations.
Efficacy and safety of available antiepilepticdrugs Failure of antiepileptic therapy can consist of incomplete seizure control without side effects, complete seizure control possible only with side effects, or incomplete seizure control with persistent side effect. Antiepileptic drugs do not differ much in terms of efficacy, but they do have different types and degrees of toxicity. Often, efficacy and safety are analyzed separately, but no therapy can be assessed adequately, unless the risks and the benefits are always evaluated together. This is best expressed as a therapeutic index (TI) or protective index, a ratio between
23
Bourgeois a quantative assessment of seizure reduction and a quantative assessment of undesirable side effects. As we will see, there is no universal TI for any drug that would apply to all patients. The TI of a drug may be different in every patient and, in the same patient. it may vary with changes in dosage or with time. In everyday practice. the TI cannot be expressed in units or precise numbers, but at least four different TI’S can be distinguished for practical purposes: 1. The TI can be “neutral”, which means that there is no therapeutic effect and no evidence of toxicity: 2. The TI can be “1” when there is a therapeutic response with corresponding “acceptable” toxicity; 3. The TI can be > 1, indicating that there is a good response with little or no toxicity; 4. All too often, the TI is < 1, when objective assessment reveals that the patient has actually not experienced any decrease in seizure frequency, but clearly experiences toxicity, or when toxicity is greater than efficacy. The reason why a TI
