Autism and Cognition Within Epilepsy: Social Matters

Abstract

The association of epilepsy, autism spectrum disorders (ASD), and intellectual disability (ID) is well recognized. There is a wide range of social-cognitive deficits that can be identified in epilepsy over the life-span, from ASD in infants with an epileptic encephalopathy, to social-cognitive impairments affecting social interaction and comprehension in those with normal nonsocial cognitive function. Identifying ASD and social-cognitive deficits is an important aspect of comprehensive epilepsy care. There are behavioral and educational interventions that exist to treat ASD and social-cognitive deficits. These behavioral, communication, and educational interventions, in conjunction with medications to treat the seizures, should be considered an integral part of the comprehensive management of epilepsy throughout the life-span. The following are the key points of this review:

1. Autism spectrum disorders and social-cognitive deficits are associated with epilepsy throughout the life-span, and identification of these deficits is an important part of epilepsy care.

2. Children with an epileptic encephalopathy such as infantile spasms are at high risk for developing ASD, and the social-cognitive deficits that precede ASD may be recognized in the first year of life.

3. In epilepsy, the likelihood of developing autism spectrum disorders is highest in those with ID, but there is a wide spectrum of manifestations, from ASD in children with epilepsy and ID, to social-cognitive impairments affecting social interaction and comprehension in those with normal nonsocial cognitive function.

4. Implementation of behavioral, communication, and educational interventions that exist to treat ASD and social-cognitive deficits, along with medications to treat the seizures, should be considered an important part of the comprehensive management of epilepsy throughout the life-span.

Historically, the relationship of epilepsy to autism spectrum disorders (ASD) has focused on the recognition and impact of epilepsy on ASD. That social-cognitive and communication deficits have an impact on epilepsy has received less attention and study. ASD is the current terminology used to define a heterogeneous group of neurodevelopmental disorders characterized by deficits in social-communication and social-interaction skills and by a restricted and repetitive pattern of behaviors, interests, and activity. ASD is a descriptive clinical term independent of biological cause, and the patterns of behavior that characterize ASD are dimensional in nature and change over time (1). Central to the definition of ASD are problems in social cognition and communication that range in severity, from no understanding of social interaction and no system of communication to more subtle deficits in social-cognitive reasoning and in pragmatic deficits in linguistic skills. The purpose of this brief review is to emphasize the importance of early identification of ASD and social-cognitive deficits in individuals with epilepsy throughout the life-span and to highlight the importance of implementing educational and behavioral strategies to ameliorate social-cognitive deficits as part of the comprehensive care of epilepsy.

ASD First, Then Epilepsy

Multiple studies have established that intellectual disability (ID) is the major risk factor for epilepsy in children with ASD (2). Meta-analysis studies in different cohorts estimate the risk for epilepsy in children with ASD without ID at 8%, with risk increasing to 20% in those with ID (3, 4). Among children with ASD and IQs above 70, approximately 4% develop epilepsy (5). The only other consistent risk factor of developing epilepsy in ASD besides IQ is age at ascertainment: in a population of children diagnosed with ASD in the first decade, it was only after age 10 years that the majority of seizures developed (6). In the largest sample studied to date (drawn from three genetic database populations and one epidemiologic population), of 5,815 children first diagnosed with ASD, the two major risk factors for associated epilepsy were IQ and age (7). That study found that the average prevalence of epilepsy was 12 percent and reached 26% by adolescence. Furthermore, one SD increase in IQ decreased the odds of epilepsy by 47% (7). Developmental regression was not a risk factor for developing epilepsy in that sample of children whose first diagnosis was ASD. The temporal relationship of epilepsy to ASD and numerous clinical and animal studies suggest that epilepsy is not a primary cause of ASD, nor is ASD an epileptic encephalopathy; instead, there is growing consensus that shared mechanisms account for the co-occurrence of epilepsy, ASD, and ID (8).

Epilepsy First, Then ASD

ASD is not an epileptic encephalopathy, yet children with an epileptic encephalopathy commonly have ASD (9). In the same manner that studies of children first diagnosed with ASD show that the degree of ID is a major risk factor for developing epilepsy; the corollary is also true, given that individuals with epilepsy and ID are more likely to have coexisting ASD. In a population-based study of children with seizures in the first year of life, exclusive of infantile spasms, 7% of them went on to develop ASD, which was associated with ID in all of them (10). In the children with infantile spasms from this same population, 35% (6 of 17 children) developed ASD, all with severe ID (11). In a large community-based cohort of childhood-onset epilepsy (n = 555) followed prospectively, 30% of children with infantile spasms and ID had a diagnosis of ASD (12). This study found that in a population of children with epilepsy, infantile spasms and ID are independent risk factors for the development of ASD. In a recent study of 236 children with epilepsy screened with multiple instruments for ASD, approximately 7% (15 of 236 children) had a clinical diagnosis of ASD, and 12 of these 15 children had other developmental delays or ID (13). This study not only found a very high rate of positive screens for ASD and other cognitive impairments in children with epilepsy but also emphasized the importance of screening children with epilepsy for ASD, as 20% of these children had a finding that required further evaluation and potential intervention.

Epilepsy, ASD, and ID: A Complex Conundrum

Whether starting with a population of children first diagnosed with ASD who go on to develop epilepsy, or starting with a population with epilepsy who go on to develop ASD, the risk of developing epilepsy is strongly associated with ID. Although ID is not a defining feature of ASD, it does modulate socio-cognitive function, communication, and behavior; negatively impacting neurodevelopmental outcomes in individuals with ASD and in those with epilepsy (8). Because of this strong association between epilepsy, ID, and ASD, it has been suggested that in children with epilepsy the risk of developing ASD is dependent on ID and that in the absence of ID, there is little evidence for a significantly increased risk of ASD in children with epilepsy (14).

From the perspective of the clinician managing epilepsy there is a need for further clarification of the dynamic relationship between epilepsy, ID, and ASD. It is important to determine the impact that ASD and social-cognitive deficits can have on epilepsy throughout the life-span independent of IQ or level of nonsocial cognitive function. In addition, it is important to identify early social-cognitive deficits that lead to ASD in infants with epilepsy and to determine how these early social deficits affect nonsocial cognitive outcomes. Furthermore, there are treatment strategies that have been successful in the management of ASD, and it is important to determine the role of these behavioral and educational interventions in children with epilepsy with and without ID.

Identifying ASD in Epilepsy: The Early Years

There is emerging evidence that early social-cognitive deficits that lead to ASD are identifiable and that in children with ASD, intervention targeting early social deficits can have a positive impact on cognitive and developmental outcomes. This is highlighted by a recent prospective study by Spurling Jeste and colleagues (15) of 40 children with tuberous sclerosis complex (TSC) in which they characterized early developmental markers of ASD in infants with TSC. They demonstrated that at 6 months of age, a group of infants with TSC differed from controls in having delays in the visual-mediated social behaviors, specifically in visual tracking and disengagement in attention, but not in language-based behaviors such as social babbling and orienting to name. At 12 months of age, infants with TSC who went on to develop ASD had more significant delays in all cognitive domains; their developmental trajectories differed from those who did not develop ASD in that their nonverbal IQ declined between 12 and 36 months. The developmental trajectories of the infants with TSC who went on to develop ASD were consistent with slowing of development, not regression of skills. The infants failed to acquire age-appropriate skills in the second and third years of life; specifically, slowing in development of visual receptive and fine motor skills. The role, if any, of epilepsy in the development of ASD was unclear as there was no difference in age at seizure onset between those who developed ASD and those who did not.

The study by Spurling Jeste and colleagues suggests that clinical risk factors for the development of ASD can be identified early on and that, at least in this small cohort of TSC infants, there is an early divergence of cognitive skills. They report that deficits in visually mediated social behaviors undermine the development of nonverbal communication skills, thereby compromising the development of typical social behavior, with a concomitant negative impact on cognitive and overall developmental outcome. The degree to which epilepsy further contributed to ASD in this small group of TSC infants, all of whom also had epilepsy and a significant proportion of whom had infantile spasms, is unclear given that some infants with TSC-ASD showed developmental gains rather than stagnation from 1 to 3 years of age. The question remains whether targeting the social-cognitive deficits that are precursors to developing ASD in children with early-onset epilepsies, such as infantile spasms, improves developmental-cognitive outcomes.

Can We Treat ASD Before It Becomes ASD? Implications for Epilepsy Management

There is some recent, albeit preliminary, evidence that interventions for social-cognitive behavioral skills may impact outcomes in ASD and that these interventions can be instituted prior to the diagnosis of ASD; that is, in infants at-risk for development of ASD (16). One study in 48 children with ASD demonstrated that a comprehensive developmental behavioral intervention for toddlers with ASD increased IQ by 15 points, improved adaptive behavior, and ameliorated the ASD diagnosis (17). Furthermore, in these 48 children with ASD, improvements in social behaviors were associated with normalized patterns of brain activity (18). A recent study pilot-tested a 12-week, low-intensity treatment with seven symptomatic (at-risk for ASD because of early socio-cognitive interventions) infants, ages 7 to 15 months, and found that the intervention-treated infants were less symptomatic than controls (19). The point here is that intervening early on, before a formal diagnosis of ASD, is feasible, and that a parent-implementation intervention in infants at-risk for ASD may have a positive impact on developmental outcomes. Although much further research is needed to evaluate the efficacy of these treatments, clinicians managing early-onset epilepsies, especially those with known poor developmental outcomes, such as an infant with an epileptic encephalopathy, need to be aware of these interventions as it is likely that these types of interventions will be an important part of the therapeutic arsenal for the comprehensive care of epilepsy.

Social-Cognitive Deficits in Epilepsy: The Childhood Years

Although ID is the major risk factor for developing ASD in children first diagnosed with epilepsy, one large community-based sample of children with epilepsy found that 2.2% of those with IQs above 80 developed ASD, which is double the expected rate of ASD in the general population (12). Taking a different perspective, Lew and colleagues (20) looked at social deficits in 47 children without ASD and with a normal IQ who were in mainstream education. The population included 20 children with generalized epilepsy with a mean age of 11 years and 6 months (SD, 2 years and 6 months) and 27 children with focal epilepsy with a mean age of 11 years and 2 months (SD 2 years and 2 months) and compared them with age-matched controls. They found that children with epilepsy had impaired social-cognitive skills with deficient pragmatic skills compared with their peers without epilepsy. Although the children in the study by Lew and colleagues did not have ASD, the pragmatic language deficits in these children with epilepsy are on a continuum with the social deficits of ASD. According to the new DSM-5 classification system, they would fall under the widely disputed category of social-communication disorders (21–23).

ASD and Social Cognition in Epilepsy: The Adult Years

In a nationally representative population-based study of individuals aged 16 years and older, (n = 7,403) in individuals with epilepsy, the prevalence of ASD was found to be 8.1%, and after adjusting for verbal IQ, an individual with epilepsy had a seven-fold increase in the odds of having an ASD (24). Epilepsy was strongly associated with ASD in adulthood, even after accounting for socio-demographic and health variables. There are several studies in adults with epilepsy demonstrating deficits in higher-order social cognition compared with cognitively matched controls (25–27) and increased ASD characteristics in the absence of the full cognitive and behavioral profile of ASD (28). These studies emphasize the importance of recognizing social-pragmatic deficits in epilepsy throughout the life-span, including in individuals with epilepsy and a normal IQ. It is heartening that interventions for these social-pragmatic deficits are being developed and researched (29) and may play a role in the comprehensive management of children (and perhaps adults) with epilepsy.

Social Matters: Concluding Thoughts

Social-cognitive deficits in epilepsy have a wide spectrum of manifestations, from ASD in children with epilepsy and ID, to social-cognitive impairments affecting social interaction and comprehension in children and adults with normal nonsocial cognitive function. Tools developed from the research in ASD can be useful for screening and diagnosing ASD within epilepsy, and for recognizing the broader autism phenotype of social-cognitive and communication deficits that can exist in individuals with epilepsy throughout the life-span. Furthermore, intervention strategies developed for ASD and social-pragmatic deficits have a positive impact on developmental outcomes independent of level of cognitive function. Although these intervention strategies have not been investigated in epilepsy, it is reasonable to hypothesize that in the future these behavioral, communication, and educational strategies for social-cognitive function may become an important aspect of the comprehensive management of epilepsy. Yes, within epilepsy, social matters.