Epilepsy and Autism: Neurodevelopmental Perspective
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- Tuchman, R. & Cuccaro, M. Curr Neurol Neurosci Rep (2011) 11: 428. doi:10.1007/s11910-011-0195-x
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Epilepsy and autism coexist in up to 20% of children with either disorder. Current studies suggest that a frequent co-occurring condition in epilepsy and autism is intellectual disability, which shows a very high prevalence in those with both autism and epilepsy. In addition, these recent studies suggest that early-onset seizures may index a group of infants at high risk for developing autism, usually with associated intellectual deficits. In this review we discuss recent advances in the conceptualization of shared anatomical and molecular mechanisms that may account for the coexistence of epilepsy, autism, and intellectual disability. A major contribution to our improved understanding of the relationship among these three phenotypes is the discovery of multiple genomic variants that cut across them as well as other neurobehavioral phenotypes. As these discoveries continue they are very likely to elucidate causal mechanisms for the various phenotypes and pinpoint biologic pathways that may be amenable to therapeutic interventions for this group of neurodevelopmental disorders.
KeywordsEpilepsy Seizures Autism Autism spectrum disorders Intellectual disability Genetics Neurodevelopmental disorders Molecular pathways
Two recent reviews of the literature on the prevalence of epilepsy in autism highlight what is known and what needs to be learned; key points from these reviews include the following: 1) the prevalence of epilepsy and autism ranges between 8% to 30%, dependent on the sample studied; 2) definitions of autism (neurodevelopmental disorder affecting primarily social communication but associated with language impairments and repetitive behaviors) and autism spectrum disorders (ASD; a term used interchangeably with autism but which includes a broader group of children including those with autistic disorder, pervasive developmental disorders not otherwise specified, and those with Asperger’s syndrome) have changed over time and impacted ascertainment; 3) the definition of epilepsy (operationally defined as having more than one seizure) and the characterization of epilepsy (ie, the clinical history available and electroencephalogram information used to confirm the diagnosis of epilepsy and classify the type of epilepsy) have varied significantly between studies and over time; 4) there are two peaks to seizure onset, one occurring early (prior to age 5 years), and a later peak starting in adolescence and continuing through adulthood; 5) a major risk factor for the coexistence of epilepsy and autism is intellectual disability; 6) there is no clear evidence that autism is caused by epilepsy, although the contribution of epilepsy and interictal epileptiform discharges to ongoing cognitive deficits in children with autism continues to be controversial and poorly understood; 7) there is evidence to suggest that when epilepsy and autism coexist in the same person, common shared anatomical and molecular mechanisms may account for both epilepsy and autism [1, 2•].
Epilepsy, like autism, is increasingly being described as a spectrum disorder to account for the multiple etiologies and variable clinical symptoms and outcomes . It follows that if epilepsy and autism are not single diseases but in fact symptom complexes, that there is no one treatment for either disorder. In this review the focus will be on the recent clinical studies on infants and children in which both epilepsy and autism coexist. The review will highlight the emerging literature suggesting that epilepsy and autism share common neurodevelopmental mechanisms.
Epilepsy and Autism: Clinical Conundrum?
In a meta-analysis of 24 reports on autism and epilepsy published from 1963 to 2006, the pooled prevalence of epilepsy was 21.4% in 1485 individuals with autism and intellectual disability versus 8% in 627 persons with autism without intellectual disability [4•]. This meta-analysis also found that the greater the intellectual disability the higher the risk for epilepsy, and that moderate to severe intellectual disability accounts for the greatest part of the statistical association between autism and epilepsy. In general, recent studies have found that individuals with autism and epilepsy have poorer cognitive (lower IQ), adaptive, behavioral, and social outcomes than those with autism without epilepsy [5, 6]. In sum, a consistent set of results show that epilepsy is the most common central nervous system disorder associated with autism, that intellectual disability is a significant risk factor for the development of epilepsy in autism, and that epilepsy accounts for increased morbidity and mortality in individuals with autism [7, 8, 9].
A risk factor that children with epilepsy share with those with autism is cognitive impairment, with the highest prevalence of epilepsy in those with severe intellectual disability . Cognitive deficits in children with epilepsy are common even in a community-based sample of children with epilepsy, where a recent study found that approximately 26% have some degree of intellectual disability . This study also found that younger age at onset of epilepsy is associated with increased vulnerability for cognitive impairment. In addition to cognitive impairments, recent studies have shown that children with epilepsy are at higher risk for social-communication, behavioral, and psychiatric disorders [12, 13]. Furthermore, an increased rate of death in epilepsy is more likely in those with treatment-refractory seizures, a group that also is likely to be associated with cognitive impairments .
It has been suggested since the 1990s that children with epilepsy and moderate to severe intellectual disability have a high prevalence of autism . However, the prevalence and risk factors of autism in populations of children with epilepsy have only recently become an area of research interest. A study done in 2005 in a tertiary epilepsy clinic using an autism-screening questionnaire reported that 32% of children had autism symptoms . In addition, children reported to have autism were more likely to be on multiple antiepileptic medications and have earlier-onset seizures (prior to age 2 years) than those with epilepsy without autism. A recent retrospective study of 519 individuals identified in a pediatric neurology clinic with onset of epilepsy up through 18 years of age found that 15% of patients met Diagnostic and Statistical Manual of Mental Disorders criteria for autism; in the 62 individuals with epilepsy and “idiopathic” autism, approximately 68% had an IQ below 70 . A new community-based study of 555 children diagnosed with epilepsy found that 28 (5%) had autism and that in the subset of children with epilepsy and estimated IQ less than 80 (a more liberal definition of intellectual disability than previous studies), the prevalence of autism was 13.8%, compared with 2.2% in those with normal cognitive abilities [18•]. Thus, in this study, we see once again that intellectual disability as well as infantile spasms were significant risk factors for autism in children with epilepsy.
Studies to date suggest that epilepsy is rarely causal in the development of autism. However, there is consensus that there is a strong association between epilepsy, autism, intellectual and motor disability in infants with an epileptic encephalopathy—a term currently used to capture the effect that epilepsy or epileptiform activity may have on cognition and behavior, independent and beyond what may be expected from the underlying brain pathology . Infants with an epileptic encephalopathy especially associated with infantile spasms are at high risk for developing autism and cognitive impairments . Although the concept of epileptic encephalopathy suggests that seizures and epileptiform activity may contribute to the associated cognitive problems, recent work has identified a number of common causal genes for epilepsy, autism, and intellectual disability, suggesting potential shared genetic mechanisms for the seizures and cognitive deficits associated with this group of epilepsies .
The complex relationship of seizures such as infantile spasms to the development of autism and intellectual disability is emphasized in a series of studies on epilepsy with onset in the first year of life [22••, 23, 24]. These studies found that 14% of infants with onset of epilepsy in the first year of life developed autism. Of significant interest was that the prevalence of autism was 46% in infants with infantile spasms and 69% in infants whose seizures were associated with brain insults that are acquired (eg, hypoxic-ischemic encephalopathy) or congenital (eg, cortical dysplasia), or specific genetic syndromes (eg, tuberous sclerosis). These studies highlight that children with seizures in the first year of life are more likely to develop autism, cognitive, and motor deficits. However, these studies do not answer why early-onset epilepsy, autism, and intellectual disability commonly converge. In addition, studies on epilepsy-autism have not been able to dissect the effects of the underlying pathology from the effect of the seizures themselves on cognitive and social skills outcomes.
Current studies suggest that epilepsy, autism, and intellectual disability commonly coexist. In addition, these recent studies suggest that early-onset seizures may index a group of infants at high risk for developing autism, usually with associated intellectual deficits. However, these studies leave us with an important clinical conundrum: what are the anatomical and molecular mechanisms, both causal and protective, that determine the development of social and cognitive deficits in children with early-onset epilepsy?
Common Neurodevelopmental Determinants: Anatomical and Molecular Mechanisms
A new direction in efforts to understand the relationship between epilepsy and autism is the study of children with early-onset seizures. Recent clinical studies, as discussed above, suggest that children with early-onset epilepsy are a high-risk group for developing autism, usually with cognitive deficits. From a basic science perspective there is evidence to support the hypothesis that the mechanisms that lead to epileptogenesis are informative to the study of autism and that shared mechanisms account for the convergence of epilepsy, autism, and intellectual disability [25•, 26, 27]. An emerging concept is that the mechanisms that lead to epilepsy may also affect the development of social cognition, or what could be referred to as sociogenesis. Epilepsy and autism are both large-scale neural network disorders caused by either a defect intrinsic to neuronal function in the context of normally wired and fully operational circuits or aberrant connectivity between neurons otherwise normal in function [28, 29]. Conceptually the development of epilepsy, autism, and the common cognitive impairments that travel with both disorders is often secondary to deficits in genes that lead to abnormalities of neurons disrupting the normal physiologic balance between excitation and inhibition and disrupting neural network function.
A common cause of epilepsy is malformations of cortical development in which focal structural lesions disrupt normal cortical organization and circuitry . In a recent comprehensive neuropathology study in 27 individuals, 13 with autism and 14 controls, evidence of cellular disorganization including heterotopias and dysplasia, reflecting abnormalities in neurogenesis and neuronal migration, were detected in 12 of the 13 (92%) autism brains and in only one of the control brains [30••]. The types of brain pathology found in this study are similar to the types of brain pathology commonly found in children with epilepsy. Seizures were present in five of the 13 subjects with autism. Intellectual disability was documented in all five individuals with epilepsy, and in four of the five individuals the seizures started at age 5 years or earlier. This important study suggests that similar neurodevelopmental pathology may account for epilepsy, autism, and intellectual disability.
An exciting new direction from a molecular mechanism perspective moves away from conceptualizing either epilepsy or autism as primary disorders to hypothesizing that the co-occurrence of autism and epilepsy is reflective of common or shared neurodevelopmental pathways . Although a modest number of genes have been implicated in epilepsy and ASD as separate disorders, there has been a sharp increase in identifying genes that appear etiologically relevant to ASD and epilepsy, as well as several other neurobehavioral phenotypes. It is this common underlying genetic etiology that provides a new direction for understanding the ASD-epilepsy relationship.
The central hypothesis now being pursued by investigators in both the autism and epilepsy communities is that abnormalities in synaptic plasticity early in development, either as the result of early seizures or genetic variants, may be a common mechanism for the development of autism and epilepsy. Although just one of several possibilities within this new conceptual framework, it allows for a new set of testable hypotheses. This emerging conceptual framework is supported by the identification of increasing numbers of genomic variants that have been implicated across diverse neurobehavioral phenotypes .
Owing in part to technological advances that permit large-scale interrogation of the genome, multiple groups have identified structural changes in the genome that appear etiologically relevant to autism, epilepsy, and several other neurobehavioral phenotypes including intellectual disability [32••]. Of greatest interest have been structural changes in the genome known as copy number variants (CNVs) that consist of deletions, duplications, or insertions at different points along the genome. Most of the CNVs of interest to the fields of epilepsy, autism, and intellectual disability have been those that occur infrequently (ie, rare variants). These CNVs are typically identified using two primary sources: genome-wide single nucleotide polymorphism (SNP) arrays and genome-wide comparative genomic hybridization arrays (CGHs). In contrast to rare variants, common variants (ie, those identified using large-scale genome-wide SNP arrays) have eluded discovery for both autism and epilepsy . This paucity of positive results owes in large part to the fact that genome-wide association studies are looking for common variants that most likely have very small effects; as such, these studies require extremely large sample sizes.
To date, both autism and epilepsy datasets have been of insufficient size. Not surprisingly, given the new understanding of the genomic landscape there has been a shift away from searching for common variants toward searching for multiple rare variants (ie, the common disease–rare variant hypothesis). The common disease–rare variant hypothesis supposes that common diseases are the result of multiple rare variants that have large functional effects. This hypothesis fits nicely with a model of disease that emphasizes disruption of key neurobiological pathways in which one could observe a range of possible phenotypes. Typically, the common disease–rare variant hypothesis focuses on a single common disease phenotype; in the study of autism and epilepsy it appears that there are a number of rare variants that confer multiple phenotypes—many of which co-occur in individuals . Again, this is a novel way of conceptualizing the relationship among neurodevelopmental phenotypes. It has been well established, as reviewed above, that autism, epilepsy, and intellectual disability co-occur. However, it is only recently that select CNVs have been found to give rise to each of these phenotypes separately as well as in various combinations .
Further evidence for the potential importance of shifting our search for rare variants is found in a review of different disease genes that have been tied to autism or autism traits [35•]. In this comprehensive review, Betancur [35•] identifies 103 disease genes that have been tied to autism or autism traits; many of these genes produce diseases in which autism features are primary, but also includes genes such as SHANK3, CNTNAP2, and NLGN4X and identifiable syndromes such as fragile X syndrome (FMR1), Rett syndrome (MECP2), and tuberous sclerosis (TSC1, TSC2), which are associated with epilepsy as well.
Although recent studies have advanced our understanding of the role played by CNVs and rare variants in autism, it is important to recognize the diversity of neurobehavioral phenotypes that accompany them. For instance, CNTNAP2, which is highly involved in cell adhesion, is not etiologically restricted to autism, and was first implicated in epilepsy with regression, and intellectual disability . Interestingly, Zweier et al. [37••] identified CNVs in CNTNAP2 and NRXN1 in approximately 1% of a small cohort (N = 179) who presented with features of Pitt-Hopkins syndrome but who were negative for TCF4. The authors suggest a common synaptic link between these two genes that may give rise to the different features including intellectual disability, autism, and epilepsy. Similar efforts are underway to dissect the role of genes such as SHANK3 and NLGNX4 as well as a host of other genes or CNVs. Similarly, a substantial portion of individuals with fragile X syndrome, Rett syndrome, and TSC all have an identifiable autism phenotype among their many clinical features, which frequently includes epilepsy and intellectual disability .
Although efforts to advance epilepsy and autism genetics continue in earnest, understanding the shared genetic contributions to epilepsy, intellectual disability, and autism is only beginning to gain traction. The role of CNVs or structural changes such as deletions, duplications, or insertions in the genome has been crucial for promoting this line of study . Several recent studies demonstrate the utility of genome-wide CNV methods in identifying candidate regions for epilepsy and autism. For instance, using genome-wide array CGHs, Mefford et al. [32••] identified 46 individuals (8.9%) with CNVs spread across the genome in a mixed epilepsy group of 517 patients (N = 399 with idiopathic generalized epilepsy [IGE]; 50 with benign childhood epilepsy with centrotemporal spikes; 68 with other idiopathic seizure disorders). Focusing on “genomic hotspots” or those areas more susceptible to recurrent rearrangements based on flanking genomic architecture, they found that 3.9% of the sample had recurrent CNVs (ie, those that appeared in multiple individuals), none of which were found in controls. Recurrent CNVs of interest were found on chromosomes 15q11.2, 15q13.3, and 16p13.11. These three regions have been tied to multiple neurobehavioral phenotypes including autism, intellectual disability, schizophrenia, and epilepsy. For example, deletions at 15q13.3 are associated with an increased risk for generalized epilepsy with a range of other phenotypes—notably autism and intellectual disability. In the Mefford et al. [32••] study, all of the individuals with deletions at 15q13.3 had IGE. According to Mulley and Mefford [40••], haploinsufficiency of CHRNA7 is thought to be a major contributor to the various neurobehavioral phenotypes, but additional genes may be involved as well. Interestingly, in a study of over 3000 patients with focal epilepsies, not a single CNV in 15q13.3 was detected . Nevertheless, aside from incomplete penetrance and variable expressivity, it has been difficult to determine why such variable phenotypes emerge from structural variants such as those described above. However, as more evidence accrues it is likely that a pattern of findings will emerge highlighting key elements within pathogenic CNVs and their modifiers. Deletions at other sites such as 15q11.2 have also been tied to predominantly generalized epilepsy as well as autism, intellectual disability, and schizophrenia [40••].
A similar picture is suggested for structural variants at 16p13.11 where we again see a range of neurobehavioral phenotypes including autism , epilepsy , and epilepsy with intellectual disability . There is a suggestion that 16p13.11 variants are more likely to result in an epilepsy phenotype versus intellectual disability or autism [39, 44]. Heinzen et al.  investigated the frequency of CNVs in a large dataset of 3812 individuals with predominantly focal (> 90%) epilepsies. Although this study examined CNVs in several known epilepsy risk regions including 15q13.1 and 15q11.2, the report emphasizes that the 16p13.11 locus represented the greatest risk variant for epilepsy in the cohort. Specifically, Heinzen et al.  identified 23 individuals with a 16p13.11 CNV. More importantly, these deletions consistently include a core set of genes including NDE1, which is believed to be involved in cortical development. Further, unlike other CNVs predisposing to various neuropsychiatric conditions and intellectual disability, this cohort did not show greater than expected frequencies of these phenotypes. Overall, although this study suggests that 16p13.11 deletions are a major risk for epilepsy with haplosufficiency as a potential mechanism, the authors hint that other modifiers may be involved in instances of broader phenotypic expression.
Like other recurrent structural changes, all of these variants appear to confer broad phenotypic susceptibility. As such, a number of reasons have been posited including different size CNVs, unmasking of functional variants within or near the deletion, or a double hit involving more than one gene [45••]. Different genes are affected in these CNVs that may give rise to phenotypic differences. However, it is equally compelling that different genes are working in concert (ie, the double hit theory described above) in which there are overlapping functional areas affected or pathways disrupted, which in turn yield diverse outcomes. In addition, are there qualitative differences in the phenotypic traits found in carriers of these CNVs?; for instance, as noted above, deletions at 15q13.3 and 15q11.2 result in primary generalized epilepsies, whereas deletions of 16p13.3 are found in individuals with both generalized and localized epilepsies [40••]. At present, our level of phenotypic specificity may not be up to the challenge of discerning clinical and biological nuances that can assist in understanding the differential contributions of the various CNVs.
Similarly, studies of CNVs in autism have yielded a number of recurring CNVs that appear to be potentially causative for an autism phenotype . In a large-scale study, Pinto et al. [47•] identified several CNVs using a genome-wide SNP array in a dataset of 996 ASD individuals and 1287 matched controls. Within this cohort, Pinto et al. [47•] identified de novo CNVs in 5.7% of ASD cases and found that cases had a significantly higher rate of rare genic CNVs. Based on the presence of CNVs in cases only, several of the de novo variants identified a number of potentially interesting candidate genes including SHANK2 and DLGAP, which share involvement with the same mechanisms implicated previously with SHANK3. In addition, SYNGAP1 has demonstrated involvement in intellectual disability. Finally, Bucan et al.  examined a large cohort of individuals with ASD from 912 multiplex families. Using genome-wide SNP array data, this study focused on examination of exonic regions (ie, regions of the genome that are believed to be of functional significance). Filtering on whether the deletion/variant was present in cases versus controls recurred in unrelated families in the autism dataset, and when replicated they identified a small set of loci including NRXN1, BZRAP1, and MDGA2. Although the NRXN1 story has been discussed previously for its role in cell adhesion, the other two loci offer new insights into the role of synaptic transmission and cell adhesion. For instance, BZRAP1 is involved in synaptic transmission and regulation of voltage-gated Ca2+ channels—the latter point being of interest to autism and epilepsy overlap. MDGA2 appears to have a high similarity to CNTN4, a gene that has been previously tied to both intellectual disability and autism.
Current evidence supports a paradigm shift regarding the pathogenic relationship of autism, epilepsy, and intellectual disability . Continued discovery of the shared genetic underpinnings of epilepsy, autism, and intellectual disability will allow us to elucidate causal mechanisms for these various phenotypes and pinpoint biologic pathways. A recent study of 32 children (16 with autism and 16 controls) used gene expression data combined with functional neuroanatomy and found a relationship between functional connectivity of long-range frontal circuits to genetic variants of CNTNAP2 . They specifically found CNTNAP2 modulates frontal lobe connectivity and as such predisposes to autism. The paradigm of using functional neuroanatomy combined with gene expression data will advance our understanding of how genes shape neuronal circuitry and how this leads to the overlap of phenotypes in complex neurodevelopmental disorders such as epilepsy, autism, and intellectual disability.
There is much to be learned regarding the complex relationship between epilepsy and autism. However, despite the complexity of both disorders, advances in technology are pointing us to potential shared mechanisms of epilepsy, autism, and intellectual disability. Further characterization of the common molecular pathways shared by this group of neurodevelopmental disorders will allow for novel therapeutic interventions, which if started early in the process of both disorders and combined with present behavioral interventions, will positively impact the outcomes of both epilepsy and autism [50•].
M. Cuccaro has received a grant from the National Institutes of Health supporting his work in autism.
Conflicts of interest: R. Tuchman: receives royalties as a co-editor for the book Autism: A Neurological Disorder of Early Brain Development, and he serves on the Scientific Advisory Committee for Autism Speaks; M. Cuccaro: none.