EEG endophenotypes in autism spectrum disorder

doi:10.1016/j.yebeh.2018.09.036

Epilepsy & Behavior

Volume 88, November 2018, Pages 341-348

https://doi.org/10.1016/j.yebeh.2018.09.036 Get rights and content

Highlights

•
Children with autism spectrum disorder (ASD) are at higher risk for developing abnormalities on EEG
•
Epilepsy in the setting of autism spectrum disorder confers worse developmental and adaptive functioning
•
Children with ASD and abnormal EEGs abnormalities on EEG were more similar to those with epilepsy than to those with normal EEG results.
•
The presence of an abnormal EEG or epilepsy in the setting of ASD suggests worse developmental and adaptive functioning.

Abstract

Objectives

The association between autism spectrum disorder (ASD) and epilepsy is well-known. Abnormalities on electroencephalography (EEG) results have been reported in patients with ASD without a history of seizures. However, little is known about the relationship between abnormalities on EEG results and the core features of ASD. The purpose of the study was to determine the relationship between the presence of epilepsy and/or abnormalities on EEG results and disease-associated impairments in young children with ASD.

Methods

Data were collected from medical records at Cincinnati Children's Hospital Medical Center (CCHMC) of patients with well-characterized ASD. Patients were subdivided into three groups: ASD without epilepsy but with abnormal EEG results, ASD without epilepsy and normal EEG results, and ASD with epilepsy. Developmental (Mullen Scales of Early Learning (MSEL)), adaptive (Vineland Adaptive Behavior Scales (VABS)), behavioral (Child Behavior Checklist), and language (Preschool Language Scales (PLS)) assessments, along with birth and developmental histories, medications, and medical comorbidities were collected. Electroencephalography data were abstracted from reports and included presence, characterization, and location of abnormalities.

Results

Analysis was performed on 443 patients with ASD. Seventy patients (15.8%) had epilepsy at the time of ASD diagnosis. Out of 372 patients with ASD and no epilepsy, 95 (25.5%) had an abnormal EEG result (67.4% epileptiform, 36.8% other abnormalities). Majority of epileptiform discharges were focal (83%) and most commonly seen in the left temporal region. The group with abnormal EEG results exhibited more impaired adaptive functioning when compared with the group with normal EEG results (p < 0.05). The group with abnormal EEG results was more similar to the group with epilepsy, differing only in expressive language (p < 0.01) and fine motor (p < 0.05) skills on the Mullen Scales. The group with epilepsy exhibited lower scores in all areas of developmental and adaptive functioning compared with the group with normal EEG results (p < 0.05). At the time of analysis, 13 patients (8 in the group with abnormal EEG results, 5 in the group with normal EEG results) developed epilepsy at a mean age of 10.5 years ± 3.3 years.

Conclusions

The presence of an abnormal EEG result or epilepsy in the setting of ASD suggests worse developmental and adaptive functioning. Further analysis will help to clarify associations and offer insight into treatment for this subpopulation without epilepsy but with abnormal EEG results.

Introduction

Autism spectrum disorder (ASD) affects approximately 1 in 59 children and is characterized by impairments in social communication, along with restrictive interests and repetitive behaviors, that emerges early in development [1], [2]. An association between ASD and epilepsy has been well-established with approximately one-third of children with ASD developing epilepsy [3], [4], [5], [6]. However, abnormalities on EEG results are frequently seen in patients with ASD who never had seizures, with rates varying from 8% to as high as 60% [7], [8], [9]. In addition, there has been interest in the potential implication that abnormalities on EEG results, in the absence of seizures, have on patients with ASD [10], [11], [12], [13], [14]. Roberto Tuchman developed the term epileptiform disorder with cognitive symptoms, which describes a subgroup of individuals with ASD who have epileptiform abnormalities on EEG results in the absence of clinical seizures; these epileptiform abnormalities are thought to be part of the language, cognitive, and behavioral dysfunctions seen in this subgroup [14]. In addition, several studies have reported on the implications of epileptiform discharges in the absence of seizures on the developing brain [15], [16].

A study performed by several members of our Division of Developmental and Behavioral Pediatrics (DDBP) at Cincinnati Children's Hospital Medical Center (CCHMC) looked at overnight EEG studies obtained on 316 children who were evaluated because of concern for delayed or abnormal language development, as well as concerns for ASD [17]. Within this group, 85 (27%) were found to have abnormal EEG results. None of the children studied had a history of clinical seizures. Out of the 85 children with an abnormal EEG result, 74 (23%) met criteria for autism or ASD, six had another developmental disorder, three had Rett syndrome, one had Down syndrome, and one had Wolf–Hirschhorn syndrome. Epileptiform abnormalities on EEG results were seen in 55 (65%) of the 85 children with 30% having epileptiform activity seen in one or both temporal lobes, 28% centrally, 23% in frontal lobes, and 8% in occipital lobes. Unfortunately, the study did not differentiate abnormalities on EEG results based on clinical diagnosis, nor was detailed data on language and its relation to the abnormalities on EEG results mentioned in the study. However, these findings support an association between abnormalities on EEG results and language deficits seen in children with ASD. Clearly, more research is needed to investigate whether abnormalities on EEG results are an epiphenomenon or play a more direct role in some of the primary features seen in ASD.

Another question that has yet to be answered is whether or not the presence of abnormalities on EEG results, as well as location and frequency, in patients with ASD indicate increased risk for later development of epilepsy. In patients with ASD, it has been historically reported that epilepsy onset occurs in a bimodal distribution, with the initial peak in early childhood and the second peak occurring in adolescence [4]. Many studies have found that epilepsy onset more frequently occurs during adolescence [18], [19], but when attempting to determine whether earlier abnormalities on EEG results are predictive of later epilepsy, results are conflicting. Bolton and colleagues did not find a correlation between the development of epilepsy and previous EEG findings. In contrast, a previous study by Hara retrospectively studied 130 patients with ASD, with ages up to 18–35 years, who had been followed for 10 years [20]. Thirty-three (25%) patients developed epilepsy with the age at onset ranging from 8 to 26 years (median age of 14 years), the majority of which (73%) had epileptiform abnormalities on EEG results prior to the onset of epilepsy. In those that developed epilepsy, it was found that the number of patients with epileptiform abnormalities also changed with age (14% with abnormalities at ages 3–7 years, 58% at ages 8–12 years, 43% at ages 13–17 years). This same study also looked at lateralization and location of epileptiform abnormalities and found a higher percentage of frontal epileptiform abnormalities in the patients that developed epilepsy.

The relationship between epilepsy, epileptiform abnormalities without seizures, and core features of ASD is poorly understood. The primary objective of this study was to investigate this relationship, through a retrospective chart review of patients seen in the DDBP at CCHMC in order to answer the questions: Do children with ASD and abnormal EEG results, without seizures, represent a unique subgroup in ASD? Can we learn anything from this subgroup of patients regarding future risk for developing epilepsy?

Section snippets

Study design

Approximately 5000 patients were identified who had been diagnosed as having ASD, which includes autism, Asperger's syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS), through DDBP. At the time of analysis, retrospective chart review of records from 875 patients had been entered into a database. Four-hundred thirty-two patient records were excluded because of not having an EEG or a history of seizures at the time of initial ASD diagnosis, leaving 443 patient

Patient characteristics

Analysis was performed on 443 patients with a diagnosis of ASD who had an EEG and/or diagnosis of epilepsy around the time of their initial ASD diagnosis (Table 1). Male-to-female ratio was 4:1 overall but approached 3:1 in the group with epilepsy, though this did not reach statistical significance (p = 0.4). The average age of ASD diagnosis was 42.3 months ± 16.0 months. Age of ASD diagnosis was younger in the group with normal EEG results than in the group with abnormal EEG results (p = 0.02)

Discussion

Autism spectrum disorder and epilepsy are highly associated with one another, with increased rates of epilepsy seen in patients with ASD [3], [5], [6], [18], [26], as well as the converse [3], [5]. Individuals with ASD and epilepsy are more likely to have abnormalities on EEG results than children with ASD without a history of seizures. However, our understanding of individuals with ASD and abnormal EEG results, without seizures, remains limited. These results indicate that young children with

Conclusions

The results of our study show evidence that in the setting of ASD, children with abnormal EEG results without seizures are more similar to children with epilepsy than to those without abnormal findings on EEG. These results have important implications on future research in this area and demonstrate the need for prospective studies that collect EEG data as part of the standard work-up for ASD regardless of concern for seizure, as well as the need for longitudinal studies to determine the

Acknowledgments

Funding for the study was provided by a grant from the Jack Rubinstein Foundation For Developmental Disabilities. Funds provided a research coordinator, Carrie Thomas, who was responsible for extracting patient data and putting information into the database.

Disclosure of conflicts of interest

None of the authors have any disclosures.

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View full text

EEG endophenotypes in autism spectrum disorder

Highlights

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Study design

Patient characteristics

Discussion

Conclusions

Acknowledgments

Disclosure of conflicts of interest

Biol Psychiatry

Brain and Development

Epilepsy Behav

Brain and Development

Brain and Development

Epilepsy Behav

Neurobiol Dis

Brain and Development

Epilepsy Behav

Brain and Development

Epilepsy Behav

Eur J Paediatr Neurol

Prevalence of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2014

MMWR Surveill Summ

Monitoring ADD. Prevalence of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2010

MMWR Surveill Summ

The incidence of seizures among children with autistic symptoms

Am J Psychiatry

EEG and seizures in autistic children and adolescents: further findings with therapeutic implications

Clin EEG Neurosci

Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates

Pediatrics

Prevalence of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2014