Social and Cognitive Outcome from Childhood-Onset Epilepsy: Do We Have Some Good News?

Commentary

Social Outcomes of Young Adults With Childhood-Onset Epilepsy: A Case-Sibling-Control Study

Baca CB, Barry F, Vickrey BG, Caplan R, Berg AT. Epilepsia 2017;58:781–791

OBJECTIVE: We aimed to compare long-term social outcomes in young adults with childhood-onset epilepsy (cases) with neurologically normal sibling controls. METHODS: Long-term social outcomes were assessed at the 15-year follow-up of the Connecticut Study of Epilepsy, a community-based prospective cohort study of children with newly diagnosed epilepsy. Young adults with childhood-onset epilepsy with complicated (abnormal neurologic exam findings, abnormal brain imaging with lesion referable to epilepsy, intellectual disability (ID; IQ < 60) or informative history of neurologic insults to which the occurrence of epilepsy might be attributed), and uncomplicated epilepsy presentations were compared to healthy sibling controls. Age, gender, and matched-pair adjusted generalized linear models stratified by complicated epilepsy and 5-year seizure-free status estimated adjusted odds ratios (aORs) and 95% confidence intervals [CIs] for each outcome. RESULTS: The 15-year follow-up included 361 individuals with epilepsy (59% of initial cases; N = 291 uncomplicated and N = 70 complicated epilepsy; mean age 22 years [standard deviation, SD 3.5]; mean epilepsy onset 6.2 years [SD 3.9]) and 173 controls. Social outcomes for cases with uncomplicated epilepsy with ≥5 years terminal remission were comparable to controls; cases with uncomplicated epilepsy <5 years seizure-free were more likely to be less productive (school/employment < 20 h/week) (aOR 3.63, 95% CI 1.83–7.20) and not to have a driver's license (aOR 6.25, 95% CI 2.85–13.72). Complicated cases with epilepsy <5 years seizure-free had worse outcomes across multiple domains; including not graduating high school (aOR 24.97, 95% CI 7.49–83.30), being un- or underemployed (<20 h/week) (aOR 11.06, 95% CI 4.44–27.57), being less productively engaged (aOR 15.71, 95% CI 6.88–35.88), and not living independently (aOR 10.24, 95% CI 3.98–26.36). Complicated cases without ID (N = 36) had worse outcomes with respect to productive engagement (aOR 6.02; 95% CI 2.48–14.58) compared to controls. Cases with complicated epilepsy were less likely to be driving compared to controls, irrespective of remission status or ID. SIGNIFICANCE: In individuals with uncomplicated childhood-onset epilepsy presentations and 5-year terminal remission, young adult social outcomes are comparable to those of sibling controls. Complicated epilepsy, notable for intellectual disability, and seizure remission status are important prognostic indicators for long-term young adult social outcomes in childhood-onset epilepsy.

Cognitive Outcome in Childhood-Onset Epilepsy: A Five-Decade Prospective Cohort Study

Karrash M, Tiitta P, Hermann B, Joutsa J, Shinnar S, Rinne J, Anttinen A, Sillanpää M. J Int Neuropsychol Soc 2017;23:332–340.

OBJECTIVES: Little is known about the very long-term cognitive outcome in patients with childhood-onset epilepsy. The aim of this unique prospective population-based cohort study was to examine cognitive outcomes in aging participants with childhood-onset epilepsy (mean onset age = 5.3 years) five decades later (mean age at follow-up = 56.5 years). METHODS: The sample consisted of 48 participants with childhood-onset epilepsy and 48 age-matched healthy controls aged 48–63 years. Thirty-six epilepsy participants were in remission and 12 continued to have seizures. Cognitive function was examined with 11 neuropsychological tests measuring language and semantic function, episodic memory, and learning, visuomotor function, executive function, and working memory. RESULTS: The risk of cognitive impairment was very high in participants with continuing seizures; odds ratio (OR) = 11.7 (95% confidence interval [CI] (2.8, 49.6), p = .0008). They exhibited worse performances across measures of language and semantic function, and visuomotor function compared to participants with remitted epilepsy and healthy controls. In the participants with remitted epilepsy, the risk of cognitive impairment was somewhat elevated, but not statistically significant; OR = 2.6 (95% CI [0.9, 7.5], p = .08). CONCLUSIONS: Our results showed that the distinction of continued versus discontinued seizures was critical for determining long-term cognitive outcome in childhood-onset epilepsy. Few participants in remission exhibited marked cognitive impairment compared to age-matched peers. However, a subgroup of participants with decades long active epilepsy, continuous seizure activity and anti-epileptic drug (AED) medication, showed clinically significant cognitive impairment and are thus in a more precarious position when entering older age.

Understandably, parents of children with epilepsy want answers regarding prognosis, placing clinicians in the difficult position of trying to predict outcome in these cases. If one looks to the basic neurosciences for answers, one finds two possible paths of prediction (1). Based on a model of cerebral plasticity, one would predict that the child's brain has the potential to adapt to the effects of the neurological insult, leading to minimal effects on development. In contrast, according to a model of brain vulnerability, one would predict a derailment of normal growth patterns, due to a depletion of neural resources and the absence of a normal blueprint to guide the path toward development. The situation becomes even more complicated in the case of epilepsy, where the causative insult is not necessarily static (as assumed by both models) and one must take into account the potential for ongoing effects of seizures and the drugs used to treat them.

Valuable information regarding clinical outcome has come from several well-orchestrated cohort studies performed at various sites across the globe (2). It is estimated that approximately 50 to 60 percent of children with epilepsy will achieve complete seizure remission, although prediction of seizure outcome in individual subjects remains a challenge. The news regarding social outcome has been less positive, with conclusions that adult social outcome is often unsatisfactory in these cases (3). The mechanisms underlying poor social outcome in adulthood remain inadequately understood.

Two recent studies have shed some new light on the topic of social and cognitive outcome from childhood-onset epilepsy. In the first study, by Baca and colleagues, outcomes were assessed in 361 young adults with epilepsy who were followed longitudinally as part of the Connecticut Study of Epilepsy. The cases had been tracked for an average of 15 years since initial diagnoses. Cases were classified as having “complicated” or “uncomplicated” epilepsy based on the presence or absence of abnormal findings on neurological exam, a lesion referable to epilepsy on brain imaging, IQ <60, or a history of neurologic insult related to the occurrence of epilepsy. These groups were compared to sibling controls using age, gender, and matched-pair adjusted linear models stratified by 5-year seizure-free status.

The mean age of the cases was 21.9 years (SD 3.5) at the time of the follow-up. The investigators examined a number of social outcome variables geared toward that age group, including employment/education, family/living arrangements, driving status, and trouble with the law. The major finding was that social outcomes for the cases with uncomplicated epilepsy with greater than 5 years of seizure remission were comparable to controls. The uncomplicated cases with less than 5 years remission were found to be less productive in terms of school and employment and to be less likely to have a driver's license. The complicated cases were found to found to have worse outcome across multiple social domains.

The second study, performed by Karrasch and colleagues, focused more on cognitive outcome in a relatively older sample. Neuropsychological testing was performed on 48 participants from the sample from Turku, Finland, a group followed longitudinally since the initial diagnosis of epilepsy back in 1964. The mean age of the sample was 56.5 years (SD 4.2) with a mean age of epilepsy onset at 5.3 years (4.5). Groups were divided into those with continued seizures (12/48, 25%) and those in remission for 5 or more years (36/48, 75%). These groups were compared to a sample of 48 controls, who had also been tracked longitudinally from childhood.

The neuropsychological battery included Finnish versions of standard tests for language, episodic memory, visuomotor function, executive function, and working memory. Patients with epilepsy diagnoses exhibited cognitive impairment in comparison to matched controls in late middle age, with primary effects on language, semantic functions, and visuo-spatial skills. Those with active epilepsy—with seizure effects and medication treatment continuing through the lifespan—exhibited a nearly 12-fold risk for cognitive impairment when compared to the remitted group, defined as performance below the 1.5 SD on ≥30% of the tests. The group with active seizures also completed fewer years of education.

Results from both studies indicate that cognitive and intellectual impairment appear to be an important variables in prediction of social outcome from childhood epilepsy, particularly in combination with the presence or absence of active seizures. While these results provide some hope regarding prediction of positive outcome in some individuals presenting with seizures during childhood, the studies fall short in accounting for the many complexities that exist in predicting social outcome and quality of life in patients with epilepsy (4).

For example, it is clear that social and economic factors can play a significant role in the social development of a child with epilepsy, independent of their seizure outcome and cognitive status. Results from a recent study indicate that an unstable family environment provides a high risk for transition problems and poor outcome in adulthood (5). Authors from the Connecticut study suggest that their findings might reflect their study sample's high level of access to and receipt of special services or, possibly, a change in trends over time, that is, persons with disabilities are afforded greater benefits and less stigma than were their predecessors. The authors also note that their definition of complicated versus uncomplicated epilepsy differed from definitions employed in other prospectively studied samples. Lower functioning in complicated cases from this study was not surprising, given that the group included subjects with significant levels of intellectual disability.

A striking finding from the Finnish study is that patients with epilepsy, as a group, demonstrated a general pattern of cognitive impairment in relation to controls. What is not addressed, however, is whether the cognitive impairment in that group represented an initial influence of the seizures developed in childhood or the effects of some form of progression over time. The findings raise the possibility that development of seizures in childhood might lower cognitive reserve, rendering the individual less able to withstand the effects of aging and disease later in life. Findings from the Finnish study indicate that cognitive reserve is diminished even more so in those who continue to experience seizures and require ongoing medical management.

In the end, the results from these studies provide some positive news for social outcome in patients with good seizure control, emphasizing the need to develop and employ effective treatment strategies for childhood-onset cases. Conversely, the observed relationship of poor social outcome with cognitive and intellectual impairment in patients with poor seizure control reinforces the evident need to incorporate these important variables in our prediction models and related interventions for this vulnerable age group.