Response to Antiseizure Medications in Adult Epilepsy Patients

Epilepsy is a heterogeneous condition that can affect individuals of different races, sexes, and ages. There are also multiple seizure types and epilepsy syndromes that can occur in individuals with epilepsy. The underlying causes of epilepsy can vary and include genetic factors, as well as various symptomatic causes such as brain injury, stroke, infections, tumors, and developmental disorders. Outcomes for individuals with epilepsy can vary widely depending on various clinical factors. The main aim in this dissertation was to study the effectiveness of antiseizure medications (ASMs) in patients with newly diagnosed epilepsy. The specific outcome assessed in this dissertation was seizure freedom. This objective involved analyzing data to determine how patient demographics and characteristics influence possibilities of obtaining seizure-freedom including factors such as ASM type and dosing.

The study cohort comprised of 459 patients, after thorough validation of epilepsy diagnosis. Oxcarbazepine (OXC) was the most used ASM, either as monotherapy or polytherapy, in 380 patients. Firstly, we evaluated interaction among the efficacy, tolerability, and overall effectiveness of the first ASM in patients 16 years or older with newly diagnosed epilepsy. At least one year seizure freedom was achieved in 73% of males and 60% of females with first ASM. The seizure freedom rate for focal epilepsy was 67%, with no significant difference observed between different ASMs. The study also found that patients with structural and unknownetiology had seizure freedom rates of 61.5% and 75.3%, respectively. Epileptiform activity on EEG in patients with focal epilepsy decreased the odds of achieving seizure freedom in adjusted logistic regression models.

The second study revealed that the overall seizure freedom rate with the first or subsequent ASMs was 88.0%, meaning that 404 out of 459 patients achieved seizure freedom. The rate of drug-resistant epilepsy (DRE), when defined as the failure of two ASMs for any reason, was 20.0%, and according to the International League Against Epilepsy (ILAE) definition of DRE, it was 16.3%. After failing the first ASM, 63.6% of patients (96/151) became seizure-free with subsequent ASMs and tried an average of 1.9 ASMs (range 1-5). Of the patients who achieved 1-year seizure freedom, 10.1% (41/404) were on polytherapy. The efficacy of the different ASMs was largely similar, but ASMs that enhanced GABA-mediated inhibitory neurotransmission had the lowest seizure freedom rate. All patients with primary generalized epilepsy were seizure-free.

The third study demonstrated that the doses of ASMs associated with seizure freedom in patients with epilepsy receiving OXC were influenced by age, sex, and seizure type. The largest dose difference was observed between males aged ≤60 years and females aged >60 years, 1071 mg and 763 mg, respectively. The dosing strategy should be stratified according to the clinical factors recognized in our study. In older patients 600 mg of OXC would be the primary dosing target, which is only two thirds of the dosing strategy for patients under 60 years with much less potential for side- effects in the elderly patient group.

Finally, we investigated ASM doses required to achieve seizure-freedom and their correlation with the World Health Organization’s (WHO) defined daily doses (DDDs). The mean prescribed doses (PDDs) and PDD/DDD ratio of the most used ASMs, i.e., OXC, Carbamazepine (CBZ), and Valproic acid (VPA), differed significantly between seizure-free and non-seizure-free status (992 mg and 0.99 vs 1132 mg and 1.13; 547 mg and 0.55 vs 659 mg and 0.66; and 953 mg and 0.64 vs 1260 mg and 0.84, respectively). The higher PDD/DDD ratio of OXC (0.99) than that of CBZ or VPA renders a generalized PDD/DDD comparison highly problematic. Furthermore, the study found that patients who failed an OXC dose of ≤ 900 mg had a higher likelihood of achieving seizure freedom compared to those who failed a higher dose of OXC.