Elsevier

Brain and Development

Volume 32, Issue 9, October 2010, Pages 709-718
Brain and Development

Review article
Autism and epilepsy: Historical perspective

https://doi.org/10.1016/j.braindev.2010.04.008Get rights and content

Abstract

Autism spectrum disorders (ASD) and epilepsy co-occur in approximately 30% of individuals with either ASD or epilepsy. While there is no single unifying ASD–epilepsy phenotype, understanding potential commonalities in subgroups of children with an ASD–epilepsy phenotype will help us disentangle the pathophysiology of both ASD and epilepsy. Throughout this brief historical perspective we selectively review critical trends in ASD–epilepsy research and highlight challenges to clinical and research efforts including terminology, heterogeneity of both ASD and epilepsy, and lack of careful characterization of children affected with both ASD and epilepsy. These complex issues continue to burden research on the diagnosis, neurobiology and management of children with ASD and epilepsy. A key concept that has emerged during the past 40 years is the strong association between intellectual disability and a higher prevalence of epilepsy in individuals with ASD. In addition, the two peaks of seizure onset, one in early childhood and one in adolescence and continuing through adulthood may be unique to individuals with ASD. The overlap of language and autistic regression to epilepsy, EEG epileptiform activity, sleep, and to epileptic encephalopathies such as Landau–Kleffner syndrome continue to be controversial areas of research and of clinical interest. An emerging consensus is that shared developmental genetic, molecular and pathophysiological mechanisms exist and account for the common co-occurrence of ASD and epilepsy.

Introduction

The relationship of autism to epilepsy has been an area of scientific interest for decades. Autism was tied to epilepsy in Kanner’s initial description of autism over 60 years ago [1], [2] and further highlighted in his follow-up discussions in 1971 [3]. The initial studies on the relationship of autism to epilepsy and to electroencephalogram (EEG) abnormalities in the 1960s [4], [5], [6], [7] were among the first to suggest that autism was a disorder of brain function. It was also during the 1960s that epilepsy was classified as a neurological versus mental disorder in the WHO classification system for epilepsy [8]. These seminal events mark critical periods for clinical and scientific investigation of autism and epilepsy as both separate and overlapping disorders.

Despite the early recognition of both autism and epilepsy as neurobiologic disorders, studies of their co-occurrence were hampered through the 1980s due in large part to the lack of adequate diagnostic criteria, particularly for autism. Early efforts to classify autism were led by Lorna Wing who introduced the concept of the “autism triad” and highlighted common impairments in social, language and repetitive behaviors among children with cognitive deficits [9]. Concurrent developments in classification systems for seizures and epilepsy [10], [11] and standardized criteria for autism during this period [12], [13] were critical for studies of the overlap in autism and epilepsy. Since that time, clinical conceptualizations of epilepsy [14] and autism spectrum disorders [15] have continued to evolve with persistent debate as to how best to classify children with autism or epilepsy as well as with both autism and epilepsy.

Section snippets

Definitions and terminology

Epilepsy is characterized by recurrent seizures. The diagnostic category of epilepsy includes multiple disorders with varying etiologies, pathophysiology and outcome [16]. Autism is a diagnostic category that includes a spectrum of disorders with fundamental impairments in social communication with no single cause or unifying explanation [17]. It is now well accepted and understood that the diagnostic constructs of autism and epilepsy represent complex disorders with tremendous clinical

Autism definition

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM IV-TR) [18] and the 10th Edition of the International Classification of Diseases (ICD 10) of the World Health Organization [19] use the terminology of Pervasive Developmental Disorder (PDD) to categorize children with qualitative impairments in three behaviorally defined domains; reciprocal social interaction, verbal and nonverbal communication, and restricted and repetitive interests. The five subtypes

Seizure, epilepsy and EEG definitions

The term seizure is used to describe clinical events characterized by paroxysmal, stereotyped, relatively brief interruptions of ongoing behavior, associated with electrographic seizure patterns [36]. Seizures are differentiated into those that are provoked secondary to an acute event such as fever, infection, trauma, or metabolic illness and those that are unprovoked (i.e., seizures that are likely to be genetic). Although epilepsy is defined as two unprovoked seizures of any type, studies on

Historical timeline

Throughout this brief historical perspective we will identify what we consider to be key concepts that have emerged during the past 40 years and that continue to be important areas of research and of clinical interest. We will highlight challenges that have hampered research on the diagnosis, neurobiology and management of children with autism and epilepsy. Our goal is to describe important scientific observations and relevant research questions within the framework of a historical timeline.

1970s and 1980s

Early work on children with ASD and epilepsy emphasized the overlap between the two disorders in time of onset (infantile or early onset versus pubertal onset), in different syndromes (e.g., tuberous sclerosis), and in the context of different states or conditions (epileptiform versus non-epileptiform EEG). In addition, the role of developmental regression as an indicator of epilepsy in autism was also investigated during these two decades. Mainly descriptive, many of the observations derived

1990s

Building on the descriptive work of the previous two decades, the investigation of ASD and epilepsy during the1990s revolved around studies of associated symptoms and efforts to further describe the features common to individuals with ASD and epilepsy. For instance, Volkmar and colleagues [72] in a study on 192 individuals with ASD, ranging in age from 2 to 33 years, found that 21% developed epilepsy with two distinct peaks one before age 6 years and one in adolescence between 11 and 18 years of

The 21st century

A review of the present literature by Spence and Schneider [92] on the role of epilepsy and epileptiform activity on ASD found prevalence estimates of epilepsy in ASD of 5–46%, with epileptiform abnormalities in as many as 60% of children with ASD, dependent on the type of EEG study done and whether patients with and without epilepsy are included. Variables such as sample ascertainment, degree of intellectual disability (IQ), idiopathic versus non-idiopathic, age and gender all contribute to

Future directions: the next decade

This brief overview of research developments in autism and epilepsy spanning the past 40 years offers a cross section of the critical issues that have been addressed and continue to be refined. The intersection of ASD and epilepsy has challenged clinicians and researchers. Clinically and at the descriptive level, it is not a significant challenge to identify ASD and epilepsy as co-occurring disorders. The challenge arises in identifying causal mechanisms, especially given that the high clinical

Acknowledgements

This paper was presented at the International Symposium on Epilepsy in Autism Spectrum Disorders and Related Conditions (The 12th Annual Meeting of the Infantile Seizure Society), Kurume Japan, May 9–10, 2009.

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