Nonadherence is a common and previously underrecognized problem for children with newly diagnosed epilepsy. Prior cross-sectional studies examining adherence in pediatric epilepsy reported nonadherence rates between 12% and 35% using self-report. These studies had multiple methodological problems including reporting mean adherence rates across the entire cohort; lack of rigorous, well-validated, objective measures of adherence14,17,23–25
; lack of prospective, longitudinal designs23–25
; and lack of a newly diagnosed homogenous, consecutive cohort of young children with epilepsy.14,23–25
These issues prevented rigorous and systematic examination of the variability and individual differences in adherence behaviors necessary to develop and implement evidence-based adherence interventions.
Given the results of our prior study demonstrating nonadherence rates of approximately 20% in the first month of therapy,11
the current results showing almost 60% of the cohort as nonadherent in the first 6 months were surprising. Socioeconomic status was the only significant predictor of nonadherence and may help identify patients at highest risk. Given that nonadherence is frequent, may compromise the benefits of drug therapy, may complicate interpretation of clinical response, and can be addressed through evidence-based interventions,10
clinicians should consider routinely assessing adherence to antiepileptic drug therapy in all children with epilepsy. Self-report measures of adherence have recently been developed for children with epilepsy26,27
and could be used in routine clinical care.
In the current study, children demonstrated significant intrapatient and interpatient variability based on objective adherence data. Five distinct groups were identified. The severe early nonadherence group reflects children who took between one-quarter and one-half of their antiepileptic drug doses in the first month of therapy and then became completely nonadherent over time. This suggests “volitional” nonadherence,28–30
wherein parents may have actively decided that their children should not take antiepileptic drugs based on reasoned decisions. Potential reasons cited in the larger literature include denial that the child has epilepsy, being seizure-free, believing that the risks of antiepileptic drugs outweigh those of seizures, fearing intolerable adverse effects, or having financial constraints. However, our data suggest that seizure frequency and adverse events played no role in determining adherence trajectories.
In contrast, the severe delayed nonadherence group initially had high adherence (90%) that gradually declined over time, with the group taking only about 20% of their antiepileptic drug doses 6 months after initiating treatment. While this group represents the smallest percentage of patients (7%) and demonstrated significant variability, this pattern may reflect caregivers who occasionally missed giving antiepileptic drug doses with no major health consequence (eg, seizure) and, thus, made decisions to discontinue antiepileptic drugs. These 2 groups represent children with epilepsy and their families who are most in need of adherence interventions focused on discussing the family’s beliefs regarding epilepsy and antiepileptic drugs and providing education about treatment misconceptions.
The moderate nonadherence group exhibited significant variability over time, with average adherence at about 70% (eg, missing 4 of 14 doses in any given week). Several factors may contribute to this pattern of adherence. For example, forgetting is the primary barrier to adherence across several pediatric populations,31,32
including pediatric epilepsy.14,24,27
The high variability in adherence may also have reflected families missing antiepileptic drug doses in blocked periods of time, such as when families go on vacation or when competing activities occur (eg, week-end sports). These families would benefit from problem-solving regarding barriers to adherence and instituting general behavioral and organizational strategies that are efficacious.10
The mild nonadherence group, conversely, demonstrated lower variability in nonadherence, with stable adherence rates at about 85%. One goal of epilepsy therapy is to attain seizure freedom for at least 2 years. Given the pharmacokinetic properties of antiepileptic drugs, including marked interpatient and intrapatient variability in blood levels and the unpredictable nature of seizures, it is unknown whether 85% adherence is sufficient to maintain the therapeutic benefit of antiepileptic drugs for this period. The target adherence threshold (ie, the minimal adherence rate necessary for symptom management) is disease-specific and undetermined for most diseases. It ranges from 80% in adult hypertension treatment12
to 95% for human immunodeficiency virus therapy13
and is unknown for adult or pediatric epilepsy. However, even mild nonadherence may have clinically important implications. In addition to the potential for continued seizures, drug toxic effects can develop if doses are increased or drugs added unnecessarily. Adherence interventions for the mild nonadherence group could potentially be delivered within the context of routine clinic visits compared with more intensive outpatient behavioral intervention. For example, psychosocial services within the Cincinnati Children’s Hospital’s new-onset seizure clinic provide brief problem-solving interventions for forgetting to take antiepileptic drugs when away from home (eg, visiting friends, grandparents), such as setting cell phone alarms or placing a few doses in the caregiver’s bag or purse.
The near-perfect adherence group, which represents less than half of the cohort (42%), demonstrated extremely stable patterns of high adherence during the first 6 months of antiepileptic drug therapy. Similar high-adherence subgroups have been identified in 2 other chronic disease populations.2,3
Families in the near-perfect adherence group have anecdotally reported incorporating antiepileptic drug administration into well-defined family routines,33,34
such as brushing teeth or eating meals. Furthermore, these families also likely have fewer barriers to adherence and, thus, are better able to manage epilepsy and its treatment.27,32
Families in the near-perfect adherence group are exemplars within clinical practice, need no intervention, and could serve as models for other families who are having difficulties administering antiepileptic drugs on a daily basis.
No seizure-related variables, including seizure type, seizure frequency, and frequency of adverse events differentiated adherence trajectory groups. Family SES was the only significant patient-specific predictor of adherence trajectories. Children with higher SES were more likely to demonstrate adherence trajectories characterized by better adherence. These results are similar to prior work in pediatric epilepsy11
and other reports in liver transplantation35
suggesting a positive association between adherence and SES. While it is not possible for clinicians to change the socioeconomic situation of families, this finding suggests the need to recognize that lack of financial resources places children with epilepsy at risk of nonadherence. Given the often intrinsic link between SES and education, it is plausible that limited financial resources have implications for both tangible (eg, inability to pay for medications) and intangible (eg, parental supervision36
) aspects that contribute to poor adherence. Thus, proactive adherence promotion efforts are particularly salient for families who are economically disadvantaged.
To our knowledge, this study is the first to examine adherence trajectories for children with epilepsy; however, several limitations are noted with implications for future research. First, while research suggests the use of large sample sizes (eg, ≥200) for GBTM, others have successfully used sample sizes consistent with ours.2,37,38
An important area for future research is a confirmatory analysis of the trajectories identified.
Second, these data represent a consecutive cohort of children between 2 and 12 years of age with newly diagnosed epilepsy; thus, results may not be generalizable to adolescent and adult samples or to individuals with recurrent seizures or treatment-resistant epilepsy. Future studies should include a larger cohort of youth with epilepsy, including adolescents, to elucidate developmental differences in adherence and examine adherence patterns for youth with treatment-resistant epilepsy. In addition, it is possible that we found no differences in seizure activity and adverse events by adherence trajectories because of the heterogeneous nature of our sample and lack of validated tools to assess adverse events in children with epilepsy and quantify seizure activity.
Third, it is plausible that adherence behaviors may have been influenced by the monitoring itself (ie, reactivity). However, adherence research has demonstrated that reactivity is negligent or short-lived, with adherence behaviors returning to baseline shortly after monitoring is initiated.39–41
Fourth, the current study examined only sociodemographic and medical factors affecting adherence trajectories. We are currently examining psychosocial factors that contribute to adherence trajectories. Such factors, including internalizing (eg, anxiety and depression) and externalizing (eg, oppositional behaviors, inattention) disorders, epilepsy-related stigma, and knowledge about epilepsy may affect adherence and shed further light on families who are at the highest risk of nonadherence.
Finally, we were unable to examine the effect of adherence trajectories on health outcomes, including seizures and health-related quality of life. Six months of therapy is too short to rigorously determine the efficacy or effectiveness of antiepileptic drug therapy in a cohort of children with a variety of seizure types and baseline seizure frequencies,42,43
let alone the effect of differential nonadherence trajectories on ultimate seizure control. However, the rate of nonadherence over the course of the first 6 months of therapy is concerning and suggests a need for intervention studies that aim to optimize adherence early in the course of therapy.