Abstract
Early Pediatric Antiepileptic Drug Nonadherence is Related to Lower Long-Term Seizure Freedom.
Modi AC, Rausch JR, Glauser TA. Neurology 2014;82:671–673
OBJECTIVE: To examine the relationship between previously identified nonadherence trajectories during the first 6 months of antiepileptic drug (AED) therapy and long-term seizure-free rates (defined as ≥1 year of seizure freedom at the 4 years postdiagnosis milestone) in a cohort of children with newly diagnosed epilepsy. METHODS: A prospective longitudinal observational study of AED adherence and seizure freedom in a consecutive cohort of 124 children (ages 2–12 years) with newly diagnosed epilepsy was conducted. The association between previously identified AED adherence trajectories (i.e., near-perfect adherence [e.g., average adherence = 96.8%] vs nonadherent) and seizure freedom for ≥1 year at the 4 years postdiagnosis milestone was determined. RESULTS: Children who exhibited nonadherence to AED therapy in the first 6 months of treatment were 3.24 times more likely not to have achieved ≥1 year of seizure freedom at the 4 years postdiagnosis milestone compared to children in the near-perfect adherence group (χ2 = 5.13; p = 0.02). Specifically, at the 4 years postdiagnosis milestone, only 12% of children in the near-perfect adherence group were continuing to experience seizures compared to 31% of children in the nonadherent group. CONCLUSIONS: Children with epilepsy who achieved near-perfect adherence during the first 6 months of therapy experienced a higher rate of seizure freedom 4 years postdiagnosis compared with those children who demonstrated early nonadherence. This suggests that adherence intervention early in the course of treatment could play a role in improving long-term seizure freedom rates in children with epilepsy.
Commentary
Medical adherence to drug therapies involves the degree to which patients follow the recommendations of their health professionals in terms of daily dose and duration of medication use over time. The article by Modi et al. found that early adherence to antiepileptic drugs (AEDs) was associated with at least one seizure-free year during the first 4 years of follow-up. The reason for this is not explored, and the question is 1) whether this effect is due to disease modification in which adherence to the first AED modulates the epileptic process or 2) whether it is due to patterns of early almost-perfect adherence that persists over time (a possible healthy adherer effect), leading to better seizure control and, separately, patterns of early nonadherence that persist and lead to worse seizure control.
This question is not addressed in the article; however, the fuller corpus of papers from this group tells a larger story. This story begins with a cohort of 35 children seen at the new onset epilepsy seizure clinic at Cincinnati Children's Hospital Medical Center, ages 2–12 at epilepsy onset. They were given a single first AED and were followed for adherence over one month using a medication event monitoring system (MEMS) (1). Children were excluded if they had comorbidities requiring medications or major developmental disorders. Thus, the sample of childhood onset epilepsy is not generalizable to all incident epilepsy ages 2–12. Among the 35 children, overall adherence was 79.4% in the first month but there was variability: During the first 30 days of treatment, only 23% of children always took their AEDs; complete nonadherence occurred in 20% for days 1–5 and steadily declined over five–day intervals, reaching 0% in the last 5 days, an improvement over time. Nonadherence was associated with unmarried parents and low socioeconomic status (SES) (1).
Among the 124 children with incident epilepsy in the final study sample in (2) trajectories of adherence were further assessed over a six-month period: 42% had a near-perfect adherence trajectory; 26% had a mild nonadherence trajectory; 13% had a moderate nonadherence trajectory; 7% had a severe delayed nonadherence trajectory; and 13% had a severe early nonadherence trajectory. Adherence trajectories were not associated with age, sex, AED adverse events, single parenthood, number of seizures prior to the first AED, convulsive seizures at diagnosis, seizure frequency, initial and total numbers of AEDs, and who witnessed the first seizure. Interestingly, different degrees of AED adherence in the first 6 months were already detectable in the first month after initiating the first AED, suggesting consistent behavior assessed by the MEMS in the first 6 months.
The current report extends the findings over a 4-year follow-up, showing that half of the children were categorized as early nonadherers during the first 6 months of AED therapy, and such nonadherence was associated with not achieving at least 1 year of seizure freedom within the four years after AED initiation. Nonadherent children were less likely to be white (90% vs 59%; p <0.05) (2). Regrettably, there is no information on whether nonadherence (<90%) or near perfect adherence (>90%) persisted over the 4-year follow-up. In addition to the persistence of adherence/nonadherence behaviors over a 6-month period, similar information is available from a pilot feasibility and efficacy study of an adherence intervention in children with incident epilepsy identified with the same exclusion and inclusion criteria [(3) calculations based on table II]. Among the 30 children eligible for randomization after a 30-day monitoring of adherence, 19 were excluded due to their near-perfect adherence over the first 30 days of AED treatment, and 3 withdrew prior to randomization, leaving 8 children with early nonadherence who were randomized to the adherence intervention or to treatment as usual. Children with early near-perfect adherence were more likely to be non-Hispanic whites than were the randomized early nonadherent children (89.5% vs 37.5%; p <0.05) (3), similar to the current article. Among the 19 children with near perfect adherence, 5 (26.3%) fell below 90% adherence at 3–4 months after AED initiation (i.e., the end of the post-treatment follow-up period). Regrettably, this is a shorter period than assessed in the earlier study evaluating adherence trajectories over a 6-month period. Thus, we still do not know whether adherence behavior changes in the longer 4-year follow-up; therefore, it is impossible to determine whether early adherence is more likely to result in disease modification on the first AED leading to periods of seizure freedom, lasting at least 1 year, or is a result of persistent AED adherence over a longer time period.
Like epilepsy, pediatric asthma and childhood sickle cell disease also have episodic manifestations, perhaps making interventions aimed at improving adherence over time more difficult since recurrence can be unpredictable and time periods between events may be long. The proportion with nonadherence in the article by Modi et al. is similar to pediatric asthma, in which nonadherence occurs in 40 to 65 percent in studies also using electronic dosage monitoring (4), and is worse for penicillin prophalaxis in sickle cell disease where only 12% are adherent (5).
Other possible contributions to early and sustained AED nonadherence relate to aspects of the family and the medical system. Parent/caretakers are not described by educational attainment (important for health literacy), work hours, number of children in the home, insurance status, drug plans, or difficulty getting proper epilepsy care over time, leading to missed scheduled visits and delayed mediation refills. The healthcare system is not defined by the proportion seen in the clinic during follow-up versus private doctors’ offices, the time the doctor takes to explain why AED adherence is important, and the number of different doctors attending the patient over time. In contrast to seizures following a missed AED dose where parents may be more likely to ensure future doses are given as prescribed, it is possible that seizures can beget nonadherence when the parent gives all doses. This might lead to the assumption that the AED is ineffective. Before considering further intervention designs to reduce nonadherence, these factors should be considered.
There are substantial adverse outcomes of continued seizures among preteens with incident epilepsy. Some of these outcomes may reflect the greater proportion of children with continued seizures in those with AED nonadherence. In childhood onset epilepsy, continued seizures are associated with more school absences (6), poorer quality of life (7), emergency room visits (8), and mortality, including sudden unexpected death in epilepsy and accidental drowning (9). It is important that feasible and acceptable low-cost interventions be designed to reduce these adverse outcomes.