Abstract
Antiseizure medications (ASMs) were developed to treat seizures. In general, ASMs reduce excitability in the brain by either reducing the activity of excitatory receptors, or increasing the activity of inhibitory receptors. Because ASMs specifically target neuronal receptors, they can be indicated for a number of other neurodevelopmental disorders. This is a clinical PhD thesis which is composed of three interwoven studies that examines the use of ASMs in children by interrogating ASM use in children from an epidemiological perspective and indication perspective. This thesis then focuses on ASM trial design by exploring how absence seizures in children can be quantified, through examining efficacy of a novel ASM, cannabidiol (CBD).
Prior to this thesis, no information was available on the epidemiology of epilepsy in Māori and Pacific Peoples, and limited epidemiological information was available for the Oceania region. Furthermore, there was limited data on ASM use in children for other indications globally. My study methodology using the New Zealand Pharmaceuticals database enabled the ascertainment of a large population based cohort of children on ASMs which represented 48% of the New Zealand population. I was able to identify the indications for prescribing these ASMs in 94% of the cohort. I found the period prevalence of treated epilepsy in New Zealand was 3.4 per 1000, and incidence was 65.8 per 100,000 children, similar to that reported in other high-income countries. I also found New Zealand children living in the most deprived areas have a higher period prevalence of treated epilepsy, of 4.4 per 1000 children, than those living in the least deprived areas, at 2.7 per 1000 children. Ethnicity had a considerable impact on the period prevalence of epilepsy. Prevalence was similar for most ethnic groups (European/other: 3.7, 95% CI 3.4–3.9; Pacific Peoples: 3.6, 95% CI 3.2–4.1; Māori: 3.4, 95% CI 3.1–3.8) apart from Asians, who had a lower prevalence of 2.3 per 1,000 (95% CI 2.0–2.6). Interestingly, when I adjusted for socioeconomic deprivation, the prevalence of epilepsy in Māori and Pacific children became similar to the Asian children and significantly lower than the European children. My results highlight the importance of considering socioeconomic status when interpreting epilepsy rates in different ethnic groups.
By characterising how ASMs are used in New Zealand children, I found ASMs were predominately prescribed to treat seizures, accounting for 76% of all ASMs prescribed. The other indications included pain (6%), headache (5%), mental health (3%) and movement disorders (2%), which was consistent with other population based studies. I also found adolescents aged between 16 to 18 year olds were over four times more likely to be prescribed an ASM for a non-seizure indication than younger (≤6 year olds) children (31% versus 7%). Age impacted on the prescribing pattern of individual ASMs in New Zealand children, for instance levetiracetam was prescribed to a higher proportion of the ≤3 year old children (31%) compared to any other age group (14% to 19%). Interestingly, I found females of child bearing age were less likely to be prescribed valproate than any other antiseizure medication in children with epilepsy, however this was not the case of girls with non-seizure disorders. Additionally, the proportion of children receiving a new ASM compared to an old ASM was greater in children from higher than lower socioeconomic areas.
Absence seizures are typically brief and have subtle clinical signs that are easily missed. Assessing the efficacy of ASM in clinical trials is challenging due to the difficulty of robustly and accurately counting these seizures. Parental counting of absence seizures has been used in few trials exploring the efficacy of ASMs. I explored two distinct methodologies to count absence seizures in a 26 week open-label trial for CBD. One methodology, Period Count, required parents to count seizures for a specific duration of time at a set time each day. The other methodology, Day Score, required parents to report their impression of seizure frequency through a score of “none”, “some” and “lots”. I found both methodologies were effectively implemented throughout the 26 week trial. There was excellent compliance of using both methodologies, and the qualitative feedback from parents/caregivers supported the ease of using both methodologies. I found there was considerable variability in number of absence seizures each day in children with DEE. In this open-label trial in children with DEE I found a reduction in absence seizure frequency associated with CBD administration, as measured by both the Period Count and Day Score methodologies.
Overall, this thesis demonstrates: i) the impact of socioeconomic status and ethnicity on the prevalence and incidence of treated childhood epilepsy, ii) there is a need for focused ASM teratogenicity messaging for clinicians prescribing ASMs for non-seizure indications, iii) health policies need to consider socioeconomic factors which impact on ASM prescribing and iv) parental counting methodologies can be successfully utilised for assessing changes in absence seizure frequency in clinical ASM trials.