Treatment failure in patients with epilepsy -Exploring causes of ineffectiveness and adverse effects

Abstract

Epilepsy is a neurological disorder that leads to seizures affecting a variety of mental and physical functions. Antiepileptic drugs are the mainstay of treatment. However, in one third of patients treatment fails: patients keep getting seizures or experience bothersome side effects. In this thesis the two components of treatment failure in epilepsy are studied: 1. Ineffectiveness: the burden that seizures cannot be controlled with medication and 2. Adverse effects: the unwanted symptoms of antiepileptic drugs. We state that treatment response -independent of the disease or the syndrome- relies on three key actors: the patient, the drug, and the health care professional. In this thesis, the interaction and the different roles of these important modulators on treatment response in epilepsy was clarified. In the first part we illustrated that health care professional-related factors such as changes in medication regimes, and patient-related factors such as omitting medication can lead to insufficient seizure control. Also, we concluded that patients with low antiepileptic drugs serum levels have a nine times higher risk of seizures compared with patients with therapeutic antiepileptic drugs levels. Therapeutic drug monitoring is therefore a valuable tool that, once used appropriate, may prevent seizures. In the second part of this thesis gene-related causes of drug-resistant epilepsy were studied. This is an interesting phenomenon since if an association between certain genetic factors and refractory epilepsy could be confirmed, patients with epilepsy could be screened beforehand in order to optimize drug selection leading to improved seizure-control. To study pharmacogenetic associations almost 300 patients treated at one of the main tertiary epilepsy centres in the Netherlands were asked to participate. We extensively explored the association between all known variations (high resolution haplotypes) of the ABCB1 gene and drug-resistant epilepsy as well as a functional polymorphism in the SCN1A gene and drug-resistant epilepsy. No association was found for individual polymorphisms or haplotypes from ABCB1 or SCN1A and drug-resistant epilepsy. In the third part adverse effects of antiepileptic drugs are studied. For this thesis we made a selection of those that we thought were clinically relevant and often leading to therapeutic failure. Hypersensitivity reactions can be severe in patients using antiepileptic drugs; so far it was unclear why this occurs. We found that the presence of an aromatic ring as a commonality in chemical structures of antiepileptic drugs may explain hypersensitivity reactions. Aplastic anemia is a rare, but feared adverse effect of drug treatment often responsible for taking drugs from the market. We studied whether the use of antiepileptic drugs was associated with aplastic anemia. Our conclusion was that use of antiepileptic drugs is associated with a ninefold increased risk of aplastic anemia. Therefore, health care professionals should be alert to the possibility of AED-associated aplastic anemia. In conclusion, treatment failure in epilepsy has an enormous impact on daily life. In this thesis we studied causes of ineffectiveness and adverse events of AED treatment and provided suggestions for interventions in order to improve treatment response in patients with epilepsy.