Clinical characteristics of children and young adults with co-occurring autism spectrum disorder and epilepsy.

YEBEH-04154; No of Pages 8 Epilepsy & Behavior xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh

Review

Clinical characteristics of children and young adults with co-occurring autism spectrum disorder and epilepsy Christelle M. El Achkar, Sarah J. Spence ⁎ Department of Neurology, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA

a r t i c l e

i n f o

Article history: Revised 16 December 2014 Accepted 17 December 2014 Available online xxxx Keywords: Autism Autism spectrum disorder Epilepsy Seizure EEG Comorbidity

a b s t r a c t The association between autism spectrum disorder (ASD) and epilepsy has been described for decades, and yet we still lack the full understanding of this relationship both clinically and at the pathophysiologic level. This review evaluates the available data in the literature pertaining to the clinical characteristics of patients with autism spectrum disorder who develop epilepsy and, conversely, patients with epilepsy who develop autism spectrum disorder. Many studies demonstrate an increased risk of epilepsy in individuals with ASD, but rates vary widely. This variability is likely secondary to the different study methods employed, including the study population and definitions of the disorders. Established risk factors for an increased risk of epilepsy in patients with ASD include intellectual disability and female gender. There is some evidence of an increased risk of epilepsy associated with other factors such as ASD etiology (syndromic), severity of autistic features, developmental regression, and family history. No one epilepsy syndrome or seizure type has been associated, although focal or localization-related seizures are often reported. The age at seizure onset can vary from infancy to adulthood with some evidence of a bimodal age distribution. The severity and intractability of epilepsy in populations with ASD have not been well studied, and there is very little investigation of the role that epilepsy plays in the autism behavioral phenotype. There is evidence of abnormal EEGs (especially epileptiform abnormalities) in children with ASD even in the absence of clinical seizures, but very little is known about this phenomenon and what it means. The development of autism spectrum disorder in patients with epilepsy is less well studied, but there is evidence that the ASD risk is greater in those with epilepsy than in the general population. One of the risk factors is intellectual disability, and there is some evidence that the presence of a particular seizure type, infantile spasms, may increase risk, but some of the data are conflicting. We believe that one of the reasons that so little is known about this phenomenon is the lack of cross talk between researchers and clinicians alike in the two fields. We conclude that large systematic studies that employ strict ascertainment of samples using standardized definitions of both disorders, validated data collection tools, and appropriate longitudinal follow-up are needed to better shed light on certain clinical aspects of the comorbidity of ASD and epilepsy. Ideally, we could provide the optimal diagnostic and treatment services to these patients in a multidisciplinary setting with both epilepsy and neurobehavioral specialists. This article is part of a Special Issue entitled “Autism and Epilepsy”. © 2014 Published by Elsevier Inc.

1. Introduction The comorbidity of autism and epilepsy has been known since autism was first described by Leo Kanner in 1943. This paper reviews the data available in the literature on the co-occurrence of autism and epilepsy, with a primary focus on the clinical characteristics of patients. With regard to epilepsy in individuals with autism spectrum disorder, we discuss epidemiology, risk factors, epilepsy features, EEG findings, neurobehavioral correlates, and prognosis. With regard to autism ⁎ Corresponding author. Tel.: +1 857 218 5535. E-mail addresses: [email protected] (C.M. El Achkar), [email protected] (S.J. Spence).

spectrum disorder (ASD) in patients with epilepsy, we discuss epidemiology, risk factors, and issues related to screening this special population. The relationship between ASD and epilepsy remains unclear; in particular, is there a causal relationship between epilepsy and ASD (especially in early-onset epileptic encephalopathies) or are the two disorders both the result of the same underlying neuropathophysiology? There is an established literature demonstrating an increased prevalence of epilepsy in individuals with ASD well above the general population risk. However, published prevalence estimates vary widely from 2% to 46%. One of the reasons for the inconsistencies in reported rates could very well be secondary to changes and differences in how the two conditions have been defined, which could clearly impact ascertainment of these conditions.

http://dx.doi.org/10.1016/j.yebeh.2014.12.022 1525-5050/© 2014 Published by Elsevier Inc.

Please cite this article as: El Achkar CM, Spence SJ, Clinical characteristics of children and young adults with co-occurring autism spectrum disorder and epilepsy, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2014.12.022

2

C.M. El Achkar, S.J. Spence / Epilepsy & Behavior xxx (2015) xxx–xxx

Autism has always been described as a neurodevelopmental disorder of social reciprocity and communication, with a specific behavioral profile consisting of repetitive behaviors and restricted interests. It was originally added to the Diagnostic and Statistical Manual of Mental Disorders in its 3rd edition, and over time, the diagnostic criteria have undergone some significant changes. In DSM-III, the criteria were based on the original Kanner cases and were considered very strict. In DSM-IV, the spectrum was widened to include less severe forms of the disorder (pervasive developmental disorder (PDD) not otherwise specified (NOS) and Asperger disorder). In the most recent DSM-5, all the subgroups were combined into one diagnosis of autism spectrum disorder (ASD). It should be noted that the social communication deficits and behavioral profile cannot be better explained by intellectual disability, which is an especially common comorbidity in those with both autism and epilepsy [1]. The most widely used definition of epilepsy, according to the ILAE (International League Against Epilepsy), is that of a brain disorder characterized by an enduring predisposition to generate epileptic seizures. Practically, this is most commonly applied as having two unprovoked seizures occurring at least 24 hours apart. Review of the literature shows that these definitions are not always strictly adhered to. Nevertheless, defining the clinical characteristics of children with both ASD and epilepsy could be helpful in both clinical practice and research into pathophysiology. Knowing the clinical profile could help predict the co-occurrence when one of the disorders is present and possibly lead to earlier screening and diagnosis, which would aid in counseling families. Understanding the underlying mechanisms may provide insights into overlapping pathophysiology and development of specific therapies. 2. Epidemiology Over the years, the bulk of the epidemiological data has been based on retrospective studies, most of which were done on a small scale. But recently, there have been a few larger studies and even some population-based cohorts. Across the literature, the reported prevalence of epilepsy in patients with ASD ranges from 2.4% [2] to 46% [3]. In the largest studies [2,4–8], the rates ranged between 2.4% and 26%. This wide range most likely stems from the fact that data are drawn from a number of different types of samples that might employ differing definitions used for either one of the diagnoses and include differences in terms of the population ascertainment method, sample age range, and inclusion or exclusion of other co-occurring medical conditions or intellectual disability [9]. For instance, in a large hospital-based cohort of almost 35,000 patients under the age of 35 evaluated for ASD comorbidities, epilepsy was found in 19% compared to 2% of hospitalized controls [5], but in a large research cohort of patients with idiopathic ASD, epilepsy was found in only 2.4% of the patients [2]. The largest study focused on this comorbidity included almost 6000 patients from an existing research database, with epilepsy occurring in 12.5% of patients under age 17 [6]. It is noted that the higher rates are often reported from clinic-based samples. In a sample of 1000 clinic patients with ASD who had serial EEGs, 37% were found to have epilepsy [10], whereas population-based studies report lower rates from 6.6% [4] to 11.2% [7] to 22.5% [8], but it is interesting to note that there is still a wide range. 3. Clinical characteristics of epilepsy in patients with ASD 3.1. Factors associated with development of epilepsy in patients with ASD 3.1.1. Intellectual disability The presence of intellectual disability (ID) in ASD (i.e., an IQ lower than 70 with accompanying adaptive behavior deficits) is routinely associated with an increased rate of comorbid epilepsy. In a metaanalysis from 2008 which included data from published reports

between 1963 and 2006, the pooled prevalence of epilepsy before the age of 12 years in ASD with intellectual disability was 21.4%, while it was only 8% in the absence of intellectual disability [11]. A second meta-analysis from 2012, which included only studies with a followup period greater than 12 months, reported pooled percentages of 23.7% and 1.8%, respectively [12]. The strong association with ID and epilepsy may explain the lower rates of epilepsy in patients with Asperger disorder where intellect is defined to be in the normal range. It is, therefore, well established that intellectual disability is an independent risk factor for developing epilepsy in patients with ASD. However, it is important to note that even the “low” rates of epilepsy reported in those with ASD without ID are higher than the general population rate, suggesting that there is an increased risk of epilepsy in ASD even in the absence of ID.

3.1.2. Gender Most studies have shown that there is an increased risk of epilepsy in females with ASD when compared to males with ASD [3,4,13]. The meta-analysis from 2008 [11] showed that the rate of epilepsy in males was 18.5% compared to 34.5% in females. On the other hand, some studies have reported no difference between gender and prevalence of epilepsy [2,8,14], and one has shown a higher rate in males [12]. It is difficult to reconcile these inconsistencies, but it could be a function of the other risk factors within the gender groups. For instance, females with ASD are at a higher risk of intellectual disability, which might be a contributing factor.

3.1.3. Underlying etiology The prevalence of epilepsy in patients with primary or idiopathic ASD is widely reported to be less than that in cases with secondary or syndromic ASD, such as autism associated with tuberous sclerosis complex, fragile X syndrome, and other metabolic or structural neurological abnormalities, but the rate of epilepsy in patients with idiopathic ASD is still significantly higher than that in the general population. For instance, an evaluation of 72 patients with ASD showed statistically significant differences between the prevalence rates of epilepsy in those with idiopathic ASD with an IQ above 55 (3%), idiopathic ASD with an IQ below 55 (20%), and ASD described as secondary or syndromic (61%) [15]. In another study, the rate of epilepsy in the group with idiopathic ASD was significantly lower than that in the group with syndromic ASD (20% vs. 33%) [16]. Therefore, syndromic or secondary ASD appears to be another risk factor for epilepsy.

3.1.4. Regression Developmental regression is defined as the loss of a previously established skill. It is estimated that about 30% of patients with ASD will have a developmental regression which typically occurs between 18 and 24 months of age [17]. The presence of epilepsy and/or epileptiform EEG abnormalities has been postulated as a risk factor for regression; however, the data remain conflicting. This is most likely due to the confounding variables related to the patient characteristics in different studies. Many studies have reported no difference in the rates of autistic regression between children with or without epilepsy [18–23], while others found that regression is more common in those with epilepsy [16,24–26]. Most of these were smaller samples, and the data were not adjusted for the presence of intellectual disability. In a large crosssectional study, autistic regression was reported as more common in those with epilepsy (6.7%) compared to those without (3.6%); however, when the analysis was adjusted for ID, the difference was no longer significant [6]. In another sample with idiopathic ASD, investigators found no significant difference in the rates of regression between patients with intractable epilepsy and those with controlled seizures [27].



3.1.5. Severity or the subtype of ASD Some studies provide a breakdown of epilepsy prevalence among the types of ASD from the DSM-IV categorization: autistic disorder, Asperger disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS). Of note, these are all now grouped under the single diagnosis of autism spectrum disorder in DSM-5. However, in past usage, these subgroups were sometimes considered surrogates for severity within the autism spectrum, with autistic disorder being most severe, Asperger disorder being least severe, and PDD-NOS falling in the middle. Most studies report that epilepsy is more frequent in autistic disorder and PDD-NOS compared to Asperger disorder, with no statistically significant difference between autistic disorder and PDD-NOS. A large Finnish population-based study reported an epilepsy rate of 9.8% of patients with autistic disorder, 8.1% of patients with PDDNOS, and only 3.1% of patients with Asperger disorder. Some of this may be due to the association of epilepsy with ID since the rates of ID were higher in the groups with autistic disorder and PDD-NOS than in the group with Asperger disorder (28.8%, 13.8%, and only 1.3%, respectively) [4]. It is reasonable, therefore, to conclude that the incidence of epilepsy is similar in patients with autistic disorder and PDD-NOS and that it is much lower in patients with Asperger disorder. However, given that all these diagnoses fall under the umbrella of ASD, this differentiation has less of a clinical implication now. 3.1.6. Family history of ASD and/or epilepsy Autism spectrum disorder is believed to be a disorder with high heritability, and many genetic studies have focused on multiplex families (i.e., those with more than one family member affected with ASD). An investigation of epilepsy risk in a large study of multiplex families with ASD showed an epilepsy rate of 12.8% in the children with ASD and also 2.3% in the siblings without ASD, a rate more than double that of the general population. This suggests that there is a genetic burden not only for ASD and also for epilepsy in the families with more than one member affected with ASD [28]. Similarly, a longitudinal study looking into the incidence of epilepsy in ASD reported that the presence of epilepsy was independently associated with a broader autism phenotype in relatives (i.e., subthreshold autistic traits) [21]. Studies also show that a family history of epilepsy is associated with an increased risk of epilepsy in those with ASD [4,20,29] which is not surprising given the heritability of some of the epilepsy syndromes; however, at least one study did not find this to be true [21]. 3.1.7. Other risk factors A few papers have considered other risk factors or associations for the occurrence of epilepsy in ASD, including pre- and perinatal issues, developmental problems, and family histories (e.g., presence of psychiatric and neurological disease), but most of the studies had samples that were too small to draw reliable conclusions. For example, motor problems were found to be more prevalent in individuals with ASD who had comorbid epilepsy in two studies [14,30] but were not found to be associated in another [31]. One small study reported that epilepsy was associated with psychiatric problems in the mother during the pregnancy as well as with a family history of epilepsy [29]. However, perhaps stronger conclusions can be drawn from the recent Finnish population cohort study which found that the occurrence of epilepsy in ASD was significantly associated with lower gestational age, Apgar scores, and birth weight as well as family history of psychiatric disorders [4]. 3.2. Characteristics of epilepsy in ASD 3.2.1. Age at onset It has long been reported that there is a bimodal distribution regarding age at epilepsy onset in ASD, with a first peak in early childhood and a second peak in adolescence [32,33]. In a meta-analysis that only included studies with at least 12 months of follow-up [12], the pooled

3

estimates of epilepsy percentages in patients with ASD younger than 12 years were 4 times less than the prevalence in those studies reporting epilepsy in populations of patients older than 12 years. Similarly, the rates of epilepsy in samples with adults are higher [5,13,21]. In their adult follow-up study, Bolton and colleagues reported that in at least 20% of patients with epilepsy, seizures did not start until after the age of 20 years; therefore, seizure onset in patients with ASD is still possible during adulthood. Data are inconsistent with regard to whether more children experience their first seizure in the early or later peak. Several studies have shown that more have onset in early childhood [4,16], but a long-term follow-up study of a British cohort showed that more than half of the cases had seizure onset after age 10 [21]. In the large Finnish cohort [4], patients were not longitudinally followed which likely skewed the peak incidence towards the younger age groups. Age at onset may also depend on the ASD subtype. In the Finnish population cohort [4], the mean age at seizure onset was youngest for those with autistic disorder (5.5 years) and oldest for those with Asperger disorder (9.6 years), with PDD-NOS falling in between (7.2 years).

3.2.2. Seizure types There is no predominant seizure type or epilepsy syndrome that is associated with ASD. All seizure types have been reported, and different syndromes have been found in varying proportions in populations with ASD. The variability is likely related to the inclusion criteria of patients in the study, especially regarding the underlying etiology of ASD. In all of the larger studies, focal seizures with a dyscognitive component (i.e., complex partial seizures), with or without secondary generalization, were more common than primary generalized seizures. In a large population-based study of ASD [4], focal seizures were seen in 73% of patients while primary generalized seizures were seen in 27%. However, seizure type is not always well defined and this may affect rates. In a case-controlled study of 89 children with PDD-NOS, 70% of the children with ASD and epilepsy were found to have “unspecified types” of seizures and this included primary generalized epilepsy [8]. Both benign and severe epilepsy syndromes have been reported in children with ASD. In a study including 60 patients, 17.4% were found to have benign childhood epilepsy with centrotemporal spikes [20], and febrile seizures were reported to be as frequent as 33.7% [16], which is significantly higher than that of the general population. A severe infantile-onset seizure syndrome (West syndrome) has also been reported in a small percentage (5.8%) of patients [16]. The variability of epilepsy/seizure types makes it difficult to counsel families about the symptoms to look out for.

3.2.3. Seizure vs. autistic behavior Since patients with ASD often exhibit behaviors that clinically might appear concerning for seizures and every seizure type occurs in individuals with ASD, it is often difficult to tell if an event is epileptic or behavioral. Neurologists typically use a patient's unresponsiveness to verbal stimulation as a sign of a seizure, but not answering when one's name is called can be a hallmark sign of ASD. Similarly, repetitive behaviors or stereotypies can look like automatisms in complex partial seizures. A small study from an inpatient epilepsy monitoring unit reported that none of the 32 patients referred for monitoring had actual seizures recorded but some had episodes which the parents described as their typical “seizures” which were not associated with EEG changes [34]. At this time, there is no consensus about how to screen for epilepsy in individuals with ASD, but it is important that providers have a high index of suspicion when investigating unusual spells in patients with ASD. It is also advisable to discuss the signs and symptoms of seizures as well as seizure precautions with the families of children recently diagnosed with autism spectrum disorder, given the increased risk of developing epilepsy.


4


3.2.4. Seizure burden Only a few studies have reported the frequency and duration of seizures and presence or absence of the most severe seizure type, status epilepticus. The data are scarce, and the range of severity is variable. However, most clinic-based samples report rates that range from frequent (multiple seizures in a day) to rare (once yearly or less) [14,20]. Similarly, there are not a lot of reports of seizure severity or response to treatment. Some studies have shown good control with 1–2 seizure medications [20,21]. In contrast, in a retrospective review from a tertiary epilepsy center, Sansa and colleagues reported that treatment-refractory epilepsy may be common (at least 34% reported as having treatment-refractory seizures). In the subset of patients with complete treatment histories available, it appeared that more than half were found to have treatment-refractory seizures, which is higher than what is reported in the general population with epilepsy [27]. In a prospective population-based sample looking at epilepsy in adulthood, 32% were reported to have intractable epilepsy [13]. As with so much in this literature, there is tremendous variability which is likely explained by sample ascertainment bias. 3.2.5. Treatment There have been no comprehensive reviews of epilepsy treatment in individuals with ASD. Presumably, treatment choices are made based on seizure type and tolerability of medications as with any individual with epilepsy. Obviously, it is important to take into account the behavioral side effects of medication that could be seen in children with ASD when choosing therapy. Several studies have reported use of multiple antiseizure medications, vagal nerve stimulator (VNS), as well as cortical resection in appropriate cases. The response to VNS in patients with ASD was thought to be less favorable than that in patients without ASD; however, the number of patients was too low to confirm this conclusion [27]. 3.2.6. EEG findings All types of EEG abnormalities have been reported including the following: epileptiform abnormalities which are focal, multifocal, or generalized; generalized or focal slowing; excessive fast activity; and the absence of normal wakefulness or sleep patterns. The epileptiform abnormalities were focal in the majority of cases, and localization varied. It appears that either frontal [10] or temporal/centrotemporal [16,20,35] epileptiform discharges tend to be more common. However, at least one study reported a predominance of occipital spikes [36]. 3.3. Epileptiform EEG in the absence of epilepsy It should be noted that while abnormal EEGs are expected and common in individuals with epilepsy, there is a subset of children with ASD who have epileptiform discharges on EEG even in the absence of a history of clinical seizures. This phenomenon, so far, has been poorly understood but begs the following questions: Is epileptiform activity related to an increased risk of developing epilepsy? Is there any correlation between the presence of the EEG findings and the social communication deficits and behavioral abnormalities in ASD? If so, should they be the targets of treatment? 3.3.1. Rates of EEG abnormalities and associated factors In a critical review, Spence and Schneider summarized EEG findings in ASD from 12 small- to medium-sized studies and found rates to be widely variable (4–61%) [9]. This is likely secondary to a variety of methodological factors, some of which are similar to those in samples with ASD and epilepsy (e.g., age, underlying diagnosis, and comorbidities). However, the EEG data are further complicated by more of an ascertainment bias. Patients with concern for seizures tend to get more EEGs; therefore, in papers that do not separate patients with and without epilepsy, the rates of EEG abnormalities are higher [3,26]. In addition, the EEG technique itself can have a major impact. Most studies

show that prolonged studies and those including the sleep state are more sensitive in picking up abnormalities [3,22,34,35]. Similar to the epilepsy studies where epilepsy definition can impact the data, the definition of abnormal EEG can also be variable. Some abnormalities tend to signify epileptogenicity such as spikes and sharp waves, while others are related to an underlying encephalopathy or structural abnormalities such as generalized or focal slowing, respectively. Many studies did not clearly differentiate between these abnormalities, which were typically referred to as “paroxysmal EEG abnormalities”. These issues can be illustrated in a number of studies reporting rates of EEG abnormalities in ASD. Several large retrospective chart analyses have been published. All were from university-based clinic settings, at least two of which where the investigators had an interest in this phenomenon and tended to order EEGs in almost all children with ASD [19,35]. An earlier study reported lower rates of an abnormal EEG in the absence of epilepsy at 20% versus 83% in the presence of epilepsy [37]. These were mostly routine office-based EEGs, and the study noted that more EEGs were done, not surprisingly, on patients with epilepsy, possibly leading to a sampling bias. A more recent paper reported that overall, 66% of patients with ASD have an abnormal EEG (95% of patients with a history of seizures and 50% of patients with no history of seizures), with epileptiform abnormality in almost 60% of the patients [19]. That same study looked at behavioral characteristics of those with and without epileptiform EEG and found that a history of aggression or motor stereotypies was more frequent in those with epileptiform abnormalities. Kim et al. reviewed the long-term EEG monitoring data of children with ASD in their center [34] where almost all the children were referred for spells suspicious for seizures. They found 59% with epileptiform abnormalities overall and no difference in the rates of those with and without seizures. Another very large retrospective review only reported those without epilepsy, all of whom had had overnight studies and found very high epileptiform EEG rates (61%) [35]. This study highlighted the importance of obtaining sleep data since the abnormalities were only present during sleep. Developmental regression may also be a risk factor for epileptiform EEG in the absence of epilepsy, but like the association of epilepsy and regression, the data are mixed. In the largest retrospective review, there was no difference noted between the rate of regression in those with or without an epileptiform EEG. They further report that the timing of regression (before or after 18 months) also had no impact [35]. Other smaller studies found a similar lack of association [20,23,24,38]. Conversely, some studies have shown that patients with language regression tend to have a higher incidence of EEG abnormalities [26,39–41]. Again, it is hard to reconcile these differences, but they may have to do with issues related to the individual study samples. Ideally, data could be obtained from a prospective study where EEGs are collected at the time of diagnosis of ASD (regardless of seizure history or concern). This would yield unbiased prevalence data. Longitudinal follow-up could be used to determine the predictive value of an abnormal EEG in the development of later epilepsy, but this is not the currently recommended clinical practice, so it should be noted that all retrospective clinic studies are subject to bias. Obviously, these data are not consistent enough to draw conclusions regarding causal relationships with phenotype, pathophysiological overlap, or predictive/ prognostic value. However, it should be noted that the phenomenon of epileptiform EEG in the absence of seizures is relatively frequent, occurs at a significantly higher rate than in the general population where it is reported to be 1–4%, and may represent a biomarker that bears further study. 3.4. The effect of epilepsy on ASD and neurobehavioral comorbidities It is well known that patients with epilepsy are at a higher risk of behavioral and psychiatric problems, so it is important to understand the effect of the comorbid epilepsy diagnosis on individuals with ASD who already have a specific neurobehavioral phenotype. Unfortunately,



only a few studies have looked at how epilepsy impacts ASD and the data reported have not been consistent. This is likely because of a lack of prospective studies in this area. Most of these data are drawn from ongoing larger studies in ASD where those with and without epilepsy are compared in retrospect. Therefore, there is no consistency in the tools used for data collection regarding the behavioral phenotype. In one of the first studies, Turk and colleagues compared the developmental and psychological functioning in 120 children with ASD, 60 with and 60 without epilepsy, who were matched on age and verbal IQ. Using a comprehensive diagnostic interview, they found that the patients with epilepsy showed more gross and fine motor difficulties and difficulties with daily living skills. But in terms of specific ASD-related behaviors, there were only a few items that differentiated those with and without epilepsy: unusual eye contact (staring too long and hard); social interactions with peers; psychological barriers; socially shocking behavior; and less of a tendency to show an unusual fascination with objects. Interestingly, they also found that the children with ASD and epilepsy received their ASD diagnosis much later, possibly due to the epilepsy overshadowing the ASD diagnosis [30]. A larger study taken from the Simons simplex collection (a large genetic study of families with one child affected with ASD) compared those with epilepsy (n = 139) to the rest of the cohort without epilepsy (n N 2500). This study employed a wide range of phenotypic scales and initially showed that children with comorbid epilepsy showed significantly more autism symptoms and maladaptive behaviors. On the Social Responsiveness Scale (SRS), they showed worse scores on autistic mannerisms, social awareness, social cognition, social communication, and social motivation. On the Repetitive Behavior Scale — Revised (RBS-R), they showed worsened self-injurious behavior, compulsive behavior, and sameness behavior. On the Aberrant Behavior Checklist (ABC), they showed worsened stereotypy and hyperactivity. However, when the analysis was controlled for IQ, only increased hyperactivity remained significant. This suggests that the majority of the effects of epilepsy in the behavioral phenotype in ASD are driven by the presence of ID. However, when looking at only those patients with IQs in the normal range, they did find that the children with comorbid epilepsy showed more irritability and hyperactivity than the children without epilepsy [42]. Employing a different approach, Cuccarro and colleagues used latent class cluster analysis to examine the relationship between autism and epilepsy phenotypes. They found that patients with early age of recognition of ASD and odd behaviors showed a higher prevalence of epilepsy compared to the subsets of patients with later diagnosis of ASD and absence of odd behaviors. The two highest functioning clusters showed the lowest rate of epilepsy [43]. 3.5. Diagnosis and screening of epilepsy in patients with autism Screening for epilepsy in children with autism has not been well addressed in the literature. Part of the issue here is that children with ASD are often cared for by behavioral health practitioners who are not as familiar with seizure phenomena. This can lead to both over- and underrecognition. Currently, it is recommended that families of children be educated about the increased risk and what to look out for and referred to neurologists if there is concern for seizure activity. Another question is whether patients with ASD should be screened with an EEG in the absence of suspicion for seizures. At this point, there is insufficient evidence to support that obtaining an EEG would alter patient outcome, and therefore, EEG screening is only recommended if there is a clinical concern for seizures [44,45]. 3.6. Prognosis of patients with ASD and epilepsy 3.6.1. Developmental outcomes There are very few studies looking specifically into the developmental outcome of patients with ASD with and without epilepsy. It is

5

therefore unclear how epilepsy itself can affect development. The fact that epilepsy is more common in the face of comorbid intellectual disability makes this question even more complex. However, there are some data that would suggest that epilepsy is associated with overall poorer outcomes. In a study looking into medical conditions affecting the outcome of early intervention in preschool children with ASD, it was found that children without epilepsy responded more successfully to early intervention than those with epilepsy, irrespective of intervention intensity. This, however, might be explained by the greater degree of intellectual disability and neurological impairment in children with epilepsy [46]. 3.6.2. Mortality in ASD and epilepsy There is some evidence that epilepsy increases mortality in individuals with ASD. In a systematic review of studies published including at least 12 months of observation and more than 30 participants, mortality rates of individuals with ASD and epilepsy increased above those of individuals with ASD alone. Epilepsy was thought to be responsible for 7– 30% of the deaths [12]. In a large retrospective study looking specifically into the mortality in ASD with or without epilepsy, crude death rates were found to be 8 times higher in individuals with ASD and epilepsy than in those with ASD alone (6.7 vs. 0.8), but it should be noted that the rate of death in a control group with epilepsy was actually double that of those with epilepsy and autism. Sudden unexpected death in epilepsy (SUDEP) was assumed in at least 14 patients with autism and epilepsy whose brains had been donated to a specialized brain bank (Autism Tissue Program). Intractability and types of seizures were not discussed [47]. 4. Autism spectrum disorder in patients with epilepsy Most of the literature has focused on the description of the increased risk of epilepsy in the population with ASD, but certainly, the converse is also true. While there are not too many published studies, there is evidence of an increased risk of ASD in patients with epilepsy. 4.1. Epidemiology Most information regarding prevalence is based on small clinical samples which yield rate estimates that vary from 15 to 21% [48,49]. A more recent community-based prospective study of 555 children with epilepsy showed a lower prevalence of only 5% [50]. A populationbased study investigating psychiatric comorbidities of epilepsy in young adults (n = 7403) found an ASD rate of 8.1%, representing an odds ratio of autism in patients with epilepsy of 7.4 when compared to the general population [51]. Variability is likely due to differing methodologies of ASD assessment, with higher rates reported using screening tools rather than formal diagnostic evaluations. 4.2. Risk factors The risk of ASD in epilepsy may be related to several factors. There is some evidence that genetic factors play a role. One study compared those with idiopathic epilepsy, epilepsy associated with tuberous sclerosis complex (TSC), and epilepsy associated with neurofibromatosis (NF-1) and found that the risk of ASD was much higher in those with TSC compared to idiopathic but not to those with NF-1 [52]. Within the groups with TSC-associated epilepsy and idiopathic epilepsy, they found that lower IQ scores were correlated with increased ASD symptoms. Treatment-refractory epilepsy, early onset of seizures, and a severe seizure type (infantile spasms) were significant predictors for ASD symptoms, but the relationship was complex because these associations were seen only in the group with TSC-associated epilepsy. Dravet syndrome has also been associated with an increased risk of ASD. A study of 41 patients with Dravet syndrome found that 24% of patients also met DSM-IV or ICD-10 criteria for autism spectrum disorder [53].


6


Even those not meeting the criteria had some symptoms of ASD such as restricted interests, inflexible behavior, language delay, or social communication deficits. The diagnosis of ASD was associated with severe and profound intellectual disability, but the clinical characteristics of epilepsy were not different between patients with and without autism spectrum disorder. A recent study of epilepsy associated with PCDH19 mutations reports new cases and also reviews cases in the literature and shows an increased risk of ASD in this population although at varying rates [54]. In contrast, one population-based study reported a surprising finding where the rate of ASD in patients with epilepsy was higher in cases of epilepsy with unknown etiology compared to epilepsy thought to be related to structural or metabolic etiologies (37% vs. 8%) [48]. Probably, the best studied overlap between epilepsy and autism is the role of infantile spasms (IS) in the development of ASD, mainly through the model of tuberous sclerosis complex. It has long been known that children with IS have an increased risk of developing ASD [37,55]. However, the relationship is likely very complex, and there is some evidence that the association may have more to do with comorbidities of IS, such as underlying genetic factors and the presence of intellectual disability, than the seizure type itself. One study showed that IS and intellectual disability were independent risk factors for ASD [50]. Another study compared the risk of ASD in those with IS vs. other epilepsy types and found that there was no significantly increased risk of ASD in patients with IS per se but that the risk was increased in patients with symptomatic epilepsy in general [56]. These data, therefore, remain conflicting, and more controlled studies are needed. 4.3. Screening for ASD in patients with epilepsy Given the high risk of ASD in patients with epilepsy, screening can be of utmost importance in order to begin treatment promptly and optimize developmental outcomes. However, there are currently no guidelines on whether there are specific patient populations with epilepsy that should be screened and what tools to use. A few studies have addressed this issue. In one of the earlier studies, a specific ASD screening tool (the Social Communication Questionnaire (SCQ)) was administered to 97 patients with epilepsy in a tertiary epilepsy center (mean age: 12.7 years). Thirty-two percent screened positive for ASD, less than 1/3 of whom had previously been identified as having autism [57]. Another group performed an assessment of the yield of routine developmental screening in patients with epilepsy in 65 children in a hospital-based epilepsy program. Thirty-seven percent screened positive specifically for autism, and 72% screened positive for any developmental delay. However, it was important to note that the rate of ASD diagnosis after full assessment was much lower (17%) [58]. In a similar fashion, 208 clinic patients with known epilepsy were screened for ASD, and the results differed between the screening tools employed. The mCHAT (modified Checklist for Autism in Toddlers), which is a toddler screening measure, yielded 54% positive screens but only 8% went on to receive a diagnosis of ASD, whereas the SCQ yielded only 15% positive screens but 57% of those were formally diagnosed with ASD [59]. Given the high rates of ASD in those with epilepsy, it is imperative that more attention be paid to proper screening; however, the current data are not enough to establish evidencebased guidelines. Clearly, more studies are needed to determine the proper screening methods and timing of screening. 5. Conclusion In summary, we conclude that while the association between autism and epilepsy has been described for decades, we still lack a full understanding of this relationship. From the clinical standpoint, the overlap between the two disorders appears to be frequent and poses many challenges affected patients including higher risk of worsened cognitive and behavioral profiles and overall worse prognosis.

With regard to risk factors, there are several that have consistent support in the literature. Intellectual disability is associated with a higher prevalence of both epilepsy in ASD and, conversely, ASD in epilepsy. Female gender is more associated with epilepsy in ASD; however, this association may be driven by the phenomenon of lower IQs in females. Cases with idiopathic ASD appear to have a lower risk of developing epilepsy compared to those with co-occurring neurogenetic or neurological conditions (i.e., syndromic autism). The correlation between autistic regression and epilepsy remains unclear with studies showing conflicting data. A few other associated factors such as family history of either epilepsy or ASD, birth weight, gestational age, and family history of psychiatric illness have also been implicated, but there are not really enough data to draw firm conclusions. There are very few studies investigating the effect of epilepsy on ASD or related neurobehavioral phenotypes, and this is an area of much needed study. Regarding the features of epilepsy in individuals with ASD, it appears that there are at least two peaks of seizure onset: first in early childhood and second in adolescence. There are varied seizure types and epilepsy syndromes seen in individuals with ASD with complex partial seizures usually reported most commonly. In addition to the variability of seizures, behaviors that are similar to seizures are very common in patients with ASD, which adds another layer of complexity to the characterization of paroxysmal events in ASD. Less is known about the severity and treatment response of epilepsy in patients with ASD; however, there is some evidence of increased treatment refractoriness and mortality. Interictal EEG abnormalities are commonly found in patients with ASD whether or not they have seizures. However, what these abnormalities mean is still unclear. There are no available data on whether the epileptiform abnormality is actually predictive of developing epilepsy. The association between EEG abnormalities and regression remains unanswered as the available literature is divided on this topic. Current clinical recommendations are that EEGs should only be obtained if there is a clinical concern for seizures. Future research directions should include longitudinal studies of EEGs in patients with ASD to investigate whether the abnormalities are associated with any specific behavioral phenotype, predict later development of seizures, and might even be a target for treatment. There are fewer studies looking into the prevalence of ASD in patients with epilepsy. Most of the literature, however, describes an increased risk of ASD in these populations, which may be related to genetic factors or some other underlying pathophysiology. Early-onset severe epilepsy syndromes such as IS appear to increase the risk of ASD; however, the data remain conflicting on whether it is the occurrence of IS per se or the underlying etiology. Only a few studies have addressed ASD screening in populations with epilepsy, and while the samples remain small, they highlight the need for ASD screening in populations with epilepsy. Unfortunately, the optimal method for doing this remains unknown. Likewise, full diagnostic assessments of ASD in large populations with epilepsy are so far lacking. There are several standardized ASD diagnostic tools for ASD diagnosis that have become the ‘gold standard’ and could be employed. These include semistructured interviews of caregivers such as the Autism Diagnostic Interview — Revised (ADI-R) [60] and the Diagnostic Interview for Social and Communication Disorders (DISCO) [61] and a semistructured play-based assessment of the individual with autism such as the Autism Diagnostic Observation Schedule [62,63]. However, it should be noted that these tools require time and training to administer and are not meant to replace clinical diagnostic practice. In conclusion, while the phenomenon has been identified for many years, our knowledge has not advanced accordingly. This critical review of the literature shows that the research in this field has yielded inconsistent results or has not addressed some of the key questions. This is most likely because the research (and clinical care) has proceeded in discipline-specific silos. Behavioral clinicians and researchers are typically not trained in epilepsy, and neurologists/epileptologists may



have limited training in neurobehavioral disorders. The field would benefit greatly from cross talk between those in different disciplines in the clinics and labs alike. We suggest that large systematic studies employing strict ascertainment of samples using standardized definitions of both disorders, validated data collection tools, and appropriate longitudinal follow-up are needed to better shed light on certain clinical aspects of the comorbidity of ASD and epilepsy. This is necessary to inform the clinicians who take care of these patients on a daily basis. Ideally, we could provide the optimal diagnostic and treatment services to these patients in a multidisciplinary setting with both epilepsy and neurobehavioral specialists in an improved comprehensive care model. Finally, more work needs to be done at the level of investigation of the underlying pathophysiology which could ultimately contribute to translational research efforts in the development of novel treatment modalities. Conflict of interest The authors declare that there are no conflicts of interest. References [1] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. [2] Amiet C, Gourfinkel-An I, Laurent C, Carayol J, Genin B, Leguern E, et al. Epilepsy in simplex autism pedigrees is much lower than the rate in multiplex autism pedigrees. Biol Psychiatry 2013;74:e3–4. [3] Hughes JR, Melyn M. EEG and seizures in autistic children and adolescents: further findings with therapeutic implications. Clin EEG Neurosci 2005;36:15–20. [4] Jokiranta E, Sourander A, Suominen A, Timonen-Soivio L, Brown AS, Sillanpaa M. Epilepsy among children and adolescents with autism spectrum disorders: a population-based study. J Autism Dev Disord 2014;44:2547–57. [5] Kohane IS, McMurry A, Weber G, MacFadden D, Rappaport L, Kunkel L, et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One 2012;7:e33224. [6] Viscidi EW, Triche EW, Pescosolido MF, McLean RL, Joseph RM, Spence SJ, et al. Clinical characteristics of children with autism spectrum disorder and co-occurring epilepsy. PLoS One 2013;8:e67797. [7] Suren P, Bakken IJ, Aase H, Chin R, Gunnes N, Lie KK, et al. Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in Norwegian children. Pediatrics 2012;130: e152–8. [8] Mouridsen SE, Rich B, Isager T. Epilepsy and other central nervous system diseases in atypical autism: a case control study. J Neural Transm 2011;118:621–7. [9] Spence SJ, Schneider MT. The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatr Res 2009;65:599–606. [10] Yasuhara A. Correlation between EEG abnormalities and symptoms of autism spectrum disorder (ASD). Brain Dev 2010;32:791–8. [11] Amiet C, Gourfinkel-An I, Bouzamondo A, Tordjman S, Baulac M, Lechat P, et al. Epilepsy in autism is associated with intellectual disability and gender: evidence from a meta-analysis. Biol Psychiatry 2008;64:577–82. [12] Woolfenden S, Sarkozy V, Ridley G, Coory M, Williams K. A systematic review of two outcomes in autism spectrum disorder — epilepsy and mortality. Dev Med Child Neurol 2012;54:306–12. [13] Danielsson S, Gillberg IC, Billstedt E, Gillberg C, Olsson I. Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood. Epilepsia 2005;46:918–23. [14] Hara H. Autism and epilepsy: a retrospective follow-up study. Brain Dev 2007;29: 486–90. [15] Pavone P, Incorpora G, Fiumara A, Parano E, Trifiletti RR, Ruggieri M. Epilepsy is not a prominent feature of primary autism. Neuropediatrics 2004;35:207–10. [16] Parmeggiani A, Barcia G, Posar A, Raimondi E, Santucci M, Scaduto MC. Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders. Brain Dev 2010;32: 783–9. [17] Barger BD, Campbell JM, McDonough JD. Prevalence and onset of regression within autism spectrum disorders: a meta-analytic review. J Autism Dev Disord 2013;43: 817–28. [18] Tuchman RF, Rapin I. Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates. Pediatrics 1997;99:560–6. [19] Mulligan CK, Trauner DA. Incidence and behavioral correlates of epileptiform abnormalities in autism spectrum disorders. J Autism Dev Disord 2014;44:452–8. [20] Rossi PG, Parmeggiani A, Bach V, Santucci M, Visconti P. EEG features and epilepsy in patients with autism. Brain Dev 1995;17:169–74. [21] Bolton PF, Carcani-Rathwell I, Hutton J, Goode S, Howlin P, Rutter M. Epilepsy in autism: features and correlates. Br J Psychiatry 2011;198:289–94. [22] Parmeggiani A, Posar A, Antolini C, Scaduto MC, Santucci M, Giovanardi-Rossi P. Epilepsy in patients with pervasive developmental disorder not otherwise specified. J Child Neurol 2007;22:1198–203. [23] Canitano R, Luchetti A, Zappella M. Epilepsy, electroencephalographic abnormalities, and regression in children with autism. J Child Neurol 2005;20:27–31.

7

[24] Hrdlicka M, Komarek V, Propper L, Kulisek R, Zumrova A, Faladova L, et al. Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism. Eur Child Adolesc Psychiatry 2004;13:209–13. [25] Kobayashi R, Murata T. Setback phenomenon in autism and long-term prognosis. Acta Psychiatr Scand 1998;98:296–303. [26] Giannotti F, Cortesi F, Cerquiglini A, Miraglia D, Vagnoni C, Sebastiani T, et al. An investigation of sleep characteristics, EEG abnormalities and epilepsy in developmentally regressed and non-regressed children with autism. J Autism Dev Disord 2008; 38:1888–97. [27] Sansa G, Carlson C, Doyle W, Weiner HL, Bluvstein J, Barr W, et al. Medically refractory epilepsy in autism. Epilepsia 2011;52:1071–5. [28] Amiet C, Gourfinkel-An I, Laurent C, Bodeau N, Genin B, Leguern E, et al. Does epilepsy in multiplex autism pedigrees define a different subgroup in terms of clinical characteristics and genetic risk? Mol Autism 2013;4:47. [29] Ekinci O, Arman AR, Isik U, Bez Y, Berkem M. EEG abnormalities and epilepsy in autistic spectrum disorders: clinical and familial correlates. Epilepsy Behav 2010; 17:178–82. [30] Turk J, Bax M, Williams C, Amin P, Eriksson M, Gillberg C. Autism spectrum disorder in children with and without epilepsy: impact on social functioning and communication. Acta Paediatr 2009;98:675–81. [31] Ming X, Brimacombe M, Wagner GC. Prevalence of motor impairment in autism spectrum disorders. Brain Dev 2007;29:565–70. [32] Deykin EY, MacMahon B. The incidence of seizures among children with autistic symptoms. Am J Psychiatry 1979;136:1310–2. [33] Volkmar FR, Nelson DS. Seizure disorders in autism. J Am Acad Child Adolesc Psychiatry 1990;29:127–9. [34] Kim HL, Donnelly JH, Tournay AE, Book TM, Filipek P. Absence of seizures despite high prevalence of epileptiform EEG abnormalities in children with autism monitored in a tertiary care center. Epilepsia 2006;47:394–8. [35] Chez MG, Chang M, Krasne V, Coughlan C, Kominsky M, Schwartz A. Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to 2005. Epilepsy Behav 2006;8:267–71. [36] Nass R, Gross A, Devinsky O. Autism and autistic epileptiform regression with occipital spikes. Dev Med Child Neurol 1998;40:453–8. [37] Tuchman RF, Rapin I, Shinnar S. Autistic and dysphasic children II: epilepsy. Pediatrics 1991;88:1219–25. [38] Giovanardi Rossi P, Posar A, Parmeggiani A. Epilepsy in adolescents and young adults with autistic disorder. Brain Dev 2000;22:102–6. [39] Lewine JD, Andrews R, Chez M, Patil AA, Devinsky O, Smith M, et al. Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders. Pediatrics 1999;104:405–18. [40] Shinnar S, Rapin I, Arnold S, Tuchman RF, Shulman L, Ballaban-Gil K, et al. Language regression in childhood. Pediatr Neurol 2001;24:183–9. [41] Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol 2002;1:352–8. [42] Viscidi EW, Johnson AL, Spence SJ, Buka SL, Morrow EM, Triche EW. The association between epilepsy and autism symptoms and maladaptive behaviors in children with autism spectrum disorder. Autism 2013;18:996–1006. [43] Cuccaro ML, Tuchman RF, Hamilton KL, Wright HH, Abramson RK, Haines JL, et al. Exploring the relationship between autism spectrum disorder and epilepsy using latent class cluster analysis. J Autism Dev Disord 2012;42:1630–41. [44] Kagan-Kushnir T, Roberts SW, Snead III OC. Screening electroencephalograms in autism spectrum disorders: evidence-based guideline. J Child Neurol 2005;20: 197–206. [45] Filipek PA, Accardo PJ, Ashwal S, Baranek GT, Cook Jr EH, Dawson G, et al. Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology 2000;55:468–79. [46] Eriksson MA, Westerlund J, Hedvall A, Amark P, Gillberg C, Fernell E. Medical conditions affect the outcome of early intervention in preschool children with autism spectrum disorders. Eur Child Adolesc Psychiatry 2013;22:23–33. [47] Pickett J, Xiu E, Tuchman R, Dawson G, Lajonchere C. Mortality in individuals with autism, with and without epilepsy. J Child Neurol 2011;26:932–9. [48] Reilly C, Atkinson P, Das KB, Chin RF, Aylett SE, Burch V, et al. Neurobehavioral comorbidities in children with active epilepsy: a population-based study. Pediatrics 2014;133:e1586–93. [49] Matsuo M, Maeda T, Sasaki K, Ishii K, Hamasaki Y. Frequent association of autism spectrum disorder in patients with childhood onset epilepsy. Brain Dev 2010;32: 759–63. [50] Berg AT, Plioplys S, Tuchman R. Risk and correlates of autism spectrum disorder in children with epilepsy: a community-based study. J Child Neurol 2011;26:540–7. [51] Rai D, Kerr MP, McManus S, Jordanova V, Lewis G, Brugha TS. Epilepsy and psychiatric comorbidity: a nationally representative population-based study. Epilepsia 2012;53: 1095–103. [52] van Eeghen AM, Pulsifer MB, Merker VL, Neumeyer AM, van Eeghen EE, Thibert RL, et al. Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach. Dev Med Child Neurol 2013;55(2):146–53. [53] Li BM, Liu XR, Yi YH, Deng YH, Su T, Zou X, et al. Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav 2011;21:291–5. [54] van Harssel JJ, Weckhuysen S, van Kempen MJ, Hardies K, Verbeek, de Kovel CG, et al. Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders. Neurogenetics 2013;14:23–34. [55] Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013. Brain Dev 2014; 36:739–51.


8


[56] Saemundsen E, Ludvigsson P, Rafnsson V. Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life. Epilepsia 2008;49:1865–70. [57] Clarke DF, Roberts W, Daraksan M, Dupuis A, McCabe J, Wood H, et al. The prevalence of autistic spectrum disorder in children surveyed in a tertiary care epilepsy clinic. Epilepsia 2005;46:1970–7. [58] Fisher B, Dezort C, Nordli DR, Berg AT. Routine developmental and autism screening in an epilepsy care setting. Epilepsy Behav 2012;24:488–92. [59] Eom S, Fisher B, Dezort C, Berg AT. Routine developmental, autism, behavioral, and psychological screening in epilepsy care settings. Dev Med Child Neurol 2014;56: 1100–5.

[60] Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview—Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994;24:659–85. [61] Wing L. Diagnostic Interview for Social and Communication Disorders. 11th ed. Bromley, UK: Centre for Social and Communication Disorders; 2006. [62] Lord C, Risi S, Lambrecht L, Cook Jr EH, Leventhal BL, DiLavore PC, et al. The Autism Diagnostic Observation Schedule — Generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 2000;30:205–23. [63] Lord C, Rutter M, Dilavore PC, Risi S, Gotham K, Bishop SL. The Autism Diagnostic Observation Schedule 2nd Edition (ADOS-2). Los Angeles, CA: WPS Publishing; 2012.


Children with autism spectrum disorder and epilepsy.

The association between epilepsy and autism symptoms and maladaptive behaviors in children with autism spectrum disorder.

Assessing gestures in young children with autism spectrum disorder.

Atypical sulcal anatomy in young children with autism spectrum disorder.

Adults with autism spectrum disorder as behavior technicians for young children with autism: Outcomes of a behavioral skills training program.

Motor skills and calibrated autism severity in young children with autism spectrum disorder.

Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder.

Bullying Victimization, Parenting Stress, and Anxiety among Adolescents and Young Adults with Autism Spectrum Disorder.

Distinctive Rorschach profiles of young adults with schizophrenia and autism spectrum disorder.

Incontinence in children with autism spectrum disorder.

Injuries among children with autism spectrum disorder.

Obesity in children with autism spectrum disorder.

Weight Gain and Metabolic Consequences of Risperidone in Young Children With Autism Spectrum Disorder.

The Understanding of Intentions, Desires and Beliefs in Young Children with Autism Spectrum Disorder.

Emotional and behavioural problems in young children with autism spectrum disorder.

Clinical characteristics of high-functioning youth with autism spectrum disorder and anxiety.

Emotion regulation in children and adolescents with autism spectrum disorder.

Mealtime behaviors associated with consumption of unfamiliar foods by young children with autism spectrum disorder.

Quality of life of Taiwanese adults with autism spectrum disorder.

Measuring Theory of Mind in Adults with Autism Spectrum Disorder.

Impact of epilepsy and antiepileptic medications on the metabolic profile in adults with autism spectrum disorder and intellectual disabilities.

Clinical differences in children with autism spectrum disorder with and without food selectivity.

Grammatical aspect is a strength in the language comprehension of young children with autism spectrum disorder.

Use of early intervention for young children with autism spectrum disorder across Europe.