Long-term efficacy and tolerability of antiepileptic drugs in newly diagnosed epilepsy patients

Epilepsy is the most common serious chronic neurological disorder, affecting 65 million people worldwide. Antiepileptic drugs (AEDs) constitute the main treatment for epilepsy. The introduction of 14 new AEDs over the last three decades has expanded treatment options and increased the expectations about efficacy and tolerability. However, little is known about the effectiveness of new AEDs in routine clinical practice. It is also unclear whether the treatment outcomes in epilepsy have improved in recent decades as a consequence of the availability of an increasing number of AEDs. The present work attempts to provide a comprehensive evaluation of efficacy, tolerability, and retention rate of AED treatments in everyday clinical setting. This thesis is divided into six chapters, three general chapters and three result chapters (Chapter 3, 4, and 5). Chapter 1 sorts out the background of epilepsy, pharmacological management, and adverse drug reactions. The new classification of seizures and epilepsies, AED therapy, and guidelines for initiation, selection and dosing of AEDs are described. Followed by discussion of clinically relevant adverse effects of AEDs. Chapter 2 describes the study population and definition of outcome measures. Data collection and statistical analysis were presented as well. The data of this study were extracted retrospectively by reviewing the patients’ medical records. The patients were first diagnosed with epilepsy and prescribed AED treatment at the Glasgow Epilepsy Unit between Jul 1982 and Oct 2012; then they were prospectively followed up until 30 Apr 2016 with at least one year follow-up after starting AEDs therapy. The study cohort included 1,528 patients aged 18 to 93 years (median 37), 849 (56%) were men, and 1,290 (84%) had focal epilepsy. Chapter 3 evaluates efficacy of AEDs and the changes in treatment outcomes of epilepsy over the past 30 years. This was achieved by comparing the results of current analysis to the results of three analyses conducted in 1999, 2003, and 2008 on same expanding cohort (n=470, 890, and 1,098 respectively) from the Epilepsy Unit in Glasgow. The overall efficacy rate of AEDs in this study was 62% (n=941/1,528); this was comparable to what was observed in the previous analysis of 17 years ago on the same expanding cohort in which 64% (n=301/470) of newly diagnosed epilepsy patients achieved seizure-free. Likewise, the efficacy rates of different established and new AEDs were comparable. Therefore, this provides a strong evidence that treatment outcomes in epilepsy have not improved in recent decades despite the availability of increasing number of AEDs. However, the results indicated that the use of new AEDs has increased, 41% of patients continued to take the new AEDs as a monotherapy in the current study, compared to 26% in 1999. This most likely due to their advantages in terms of tolerability. This analysis also found that family history of epilepsy, more than ten pre-treatment seizures, psychiatric conditions, alcohol and recreational drugs abuse, and failure to response to two or more AEDs were significantly associated with poor seizure outcomes. In Chapter 4, the rate and predictors of intolerable adverse effects of AEDs were assessed. This study showed that 28% (n=815/2,911) of total AEDs prescriptions were discontinued because of poor tolerability. In which the most frequent problem was tiredness (5.2%, n=152/2,911) followed by poor coordination and rash, with a 2.9% (n=86) incidence for each. Among 17 different AEDs, lamotrigine was associated with the best tolerability whether it was used as monotherapy (19%, n=109/575) or as part of polytherapy (9%, n=35/387). While topiramate was associated with the highest rate of adverse effects (39%, n=32/81) among monotherapies, and retigabine had the highest rate of adverse effects (42%, n=8/19) among AEDs used as part of polytherapy. Moreover, each AED demonstrated a distinct tolerability profile; the main intolerable adverse reaction associated with lamotrigine and carbamazepine was skin rash while valproate was poorly tolerated most frequently due to tremor and weight gain. Furthermore, levetiracetam was poorly tolerated commonly due to psychiatric and behavioural side effects whereas cognitive dysfunction was the most common reason for topiramate intolerability. Beside individual AED, poor tolerability was related to patient’s susceptibility and number of co-prescribed AEDs. Prior intolerable AEDs schedule was associated with high probability to experience intolerable adverse effects at subsequent AED schedule. Likewise, female, focal epilepsy, more than ten pre-treatment seizures, and psychiatric comorbidity were significantly associated with higher rates of adverse effects. However, older AEDs usage was not significantly associated with poorer tolerability. These may present novel findings from this study as very few studies have evaluated the predictors for poor tolerability particularly non-AEDs variables. In Chapter 5, a survival analysis was performed to identify retention rates (time to discontinuation) of lamotrigine, valproate, carbamazepine, and levetiracetam monotherapies. Lamotrigine showed the highest retention rate, with median duration of therapy of 84 months. This was significantly higher than the retention times of valproate (42 months), carbamazepine (36 months), and levetiracetam (36 months); there was no significant difference in retention rates of other AEDs. However, within six months of therapy initiation, lamotrigine and carbamazepine demonstrated the highest discontinuation rates, most probably due to rash. Few observational studies have investigated the long-term retention rates of AEDs in the UK. Therefore, the current research may present novel findings in term of population as well. In Chapter 6, study strengths and limitations are presented. Clinical implications and the future directions of research in epilepsy are described as well