What is the Relationship Between Autism

Spectrum Disorders and Epilepsy?

Roberto Tuchman, MD

The association of epilepsy and autism spectrum disorders (ASD) is best understood by
examining the relationship between social cognition, nonsocial cognition, and epilepsy. The
relationship between ASD and epilepsy is bidirectional and is strongly linked to intellectual
disability (ID). The risk of developing ASD in children with epilepsy is highest in children with
early onset seizures, with a high prevalence in children with infantile spasms. The risk of
developing epilepsy in children first diagnosed with ASD is highest in those with ID. The
prevalence of seizures in ASD increases with age. When epilepsy and ASD coexist, they share
common pathophysiological mechanisms. In epilepsy with and without ID, social-cognitive
deficits are an important determinant of neurodevelopmental outcomes. Early recognition of
social deficits is an important aspect of the comprehensive management of children with
epilepsy. Treating the seizures in individuals with epilepsy and ASD is crucial but interventions
that address social-cognitive deficits are necessary to maximize neurodevelopmental out-
comes.
Semin Pediatr Neurol 24:292-300 C 2017 Elsevier Inc. All rights reserved.

Introduction In this review, the relationship between pediatric epilepsy

and ASD will be considered within a neurodevelopmental
Autism spectrum disorders (ASD) and epilepsy are both perspective and the bidirectional interaction between epilepsy
separate and overlapping disorders. Whether starting with a and ASD will be emphasized. The discussion will move away
population of children first diagnosed with ASD who go on to from the categorical diagnosis of ASD toward the specific
develop epilepsy, or starting with a population with epilepsy aspects of social cognition that impact neurodevelopmental
who go on to develop ASD, the risk of getting epilepsy is outcomes in epilepsy. The clinical populations in which both
strongly associated with global developmental delay (GDD)or epilepsy and ASD coexist will be examined from the perspec-
intellectual disability (ID).1 Although GDD or ID is not a tive of what comes first, the epilepsy or the ASD, and how this
defining feature of ASD it does modulate socio-cognitive informs us about the relationship between ASD, ID, and
function, communication, and behavior, negatively effecting epilepsy. The discussion will emphasize the shared mecha-
neurodevelopmental outcomes in individuals with ASD and in nisms accounting for the overlap between ASD, epilepsy, and
those with epilepsy.1 Any discussion about the relationship ID. Finally, the article will highlight the importance of social
between ASD and epilepsy needs to account for level of cognition in children with epilepsy and will discuss interven-
cognitive function. A better understanding of the underlying tions aimed at maximizing developmental outcomes in this
etiologies, pathways and circuits responsible for the co- group of children.
occurrence of epilepsy, ASD, and ID, should eventually result
in improved neurodevelopmental outcomes, for children with
epilepsy. This latter point is what has driven much of the recent
research on the association between epilepsy and ASD.2
Epilepsy and ASD: Defining the
Relationship
ASD and epilepsy are common pediatric neurological disorders
From the Department of Neurology, Nicklaus Children’s Hospital Miami with prevalence estimates of approximately 1% of the pop-
Children’s Health System, Miami, FL.
Address reprint requests to Roberto Tuchman, MD, Department of Neurology,
ulation and with considerable overlap between both disorders
Nicklaus Children’s Hospital Miami Children’s Health System, 2900 South and ID.3,4 The prevalence rates of ASD have increased over
Commerce Parkway, Weston, FL. E-mail: [email protected] time likely secondary to differences in diagnostic criteria,

292 https://doi.org/10.1016/j.spen.2017.10.004
1071-9091/11/& 2017 Elsevier Inc. All rights reserved.
Relationship between ASD and epilepsy 293

increased resources for intervention for ASD, and greater of mind, which represents the ability to understand our own
awareness of social-cognitive deficits in more diverse popula- thoughts, intentions, beliefs, and emotions and to recognize
tions of children.5 Both ASD and epilepsy are heterogeneous that others have beliefs, desires, intentions, and perspectives
disorders with ASD being primarily defined by deficits in social that are different from one’s own.22 Theory of mind, is an
cognition and epilepsy primarily defined by the risk of essential domain of social cognition that allows the social brain
recurring seizures. ID is not part of the categorical diagnosis to explain and predict the behavior of others.15
of ASD or of epilepsy but modulates symptom severity in Epilepsy is presently conceptualized as a spectrum disorder
both disorders.6,7 In addition, both epilepsy and ASD are emphasizing not just treatment of seizures but a comprehen-
associated with multiple neurodevelopmental conditions such sive management approach that takes into account the neuro-
as language and learning disorders, ADHD, cerebral palsy, logic, cognitive, psychological, and social consequences of this
anxiety, and mood disorders.8-11 Furthermore, epilepsy and group of disorders.23,24 For over a decade it has been
ASD frequently co-occur in chromosomal and single gene recognized that a large proportion of children with epilepsy,
syndromes.12 without evidence of other neurological problems, receive
The categorical diagnosis of ASD is based on history and special education services often before their first seizure,
clinical criteria that includes persistent deficits in social suggesting that the behavioral and cognitive abnormalities
communication and interaction across multiple domains and are not directly caused by the epilepsy.25 It is now appreciated
restricted, repetitive patterns of behavior, interest, or activities. that in children with epilepsy, cognition, is often affected
What separates ASD from other neurodevelopmental disorders around the time of the first seizure or predate it.26-28
is the social-cognitive deficit. Social cognition is broadly The relationship between epilepsy and ASD is best con-
defined as the ability to process social-emotional information ceptualized as one between epilepsy, social cognition, and
and apply it to social situations The process used for social- nonsocial cognition. In epilepsy, the 2 specific areas of the
cognitive function includes broad based circuitry in the brain broader autism phenotype that have been investigated are
used to perceive, encode, store, retrieve, and regulate informa- facial emotional recognition and theory of mind. They are core
tion about other people and ourselves.13 Social cognition is not aspects of social-cognitive function.29 In children with epilepsy
a single concept or unitary construct and as such there have social-cognitive deficits are being increasingly recognized as
been many, mostly, broad definitions of social cognition used part of the broader epilepsy phenotype.30 As will be empha-
by researchers.14 Social-cognitive processes, such as recogniz- sized below, social-cognitive deficits independent of nonsocial
ing emotions from a face are different than processing non- cognition is an important variable effecting developmental
social cognitive tasks, such as adding a list of numbers. The outcomes in children with epilepsy.
neural networks that process social and nonsocial stimuli are Studies suggest that once acquired epilepsies from infection
both distinct and overlapping at a neural and behavioral or trauma are excluded, that a significant majority of pediatric
level.13 Processing social information requires the coordinated epilepsies can be best conceptualized as neurodevelopmental
function of a widely distributed neural network, which has disorders.31 If cognitive deficits occur in epilepsy, they affect
been referred to as the social brain.15 In ASD, the social deficits, both social and nonsocial cognitive domains.7,32 Considering
have been linked to the amygdala, the superior temporal the relationship between epilepsy, ASD, and ID from a
sulcus, and the fusiform gyrus.16 neurodevelopmental perspective, acknowledges a shift in
In infants at risk for ASD, as young as 12 months, thinking for researchers and clinicians, moving away from
recognition of deficits in social cognition may include reduced the concept of whether epilepsy causes ASD or ASD causes
social attention and social communication; these early atypical epilepsy, toward the understanding of the shared neurobiology
developmental behaviors may include a decreased response to between epilepsy, social, and nonsocial cognition.1
name, reduced visual attention to socially meaningful stimuli,
and reduced use of joint attention and gestures to communi-
cate.17,18 The earliest signs of atypical social development in Epilepsy and ASD as
infants may be a decline in eye fixation starting around 2-6
months of age, leading to reduced attention to faces and face
Neurodevelopmental Disorders
like stimuli.19 Social-visual engagement, the preferential atten- Epilepsy and ASD commonly coexist in specific neurodeve-
tion given to faces and face like stimuli by infants, shapes lopmental disorders with ID such as Fragile X, tuberous
typical social-cognitive development. Social-visual engagement sclerosis complex (TSC), Rett syndrome, as well as de novo
is under genetic influence, and likely represents a neuro- copy number variations and single gene mutations, such as
developmental dimensional trait accounting for variation maternal duplications on chromosome 15q11.2-q13.1
in social information processing skills in the general (Dup15q syndrome).12,33 Genetic findings in ASD,34 specifi-
population.20 cally those with chromosomal abnormalities or mutations in
Another defining feature commonly associated with the single genes and in epilepsy35 cause impairments at the level of
social-cognitive deficits in children with ASD is joint attention, the synapse. This suggests a common causative mechanism for
defined as the group of complex behaviors used to share the both epilepsy, ASD, and ID.36 Alteration in molecular mech-
experience of objects or events with others.21 From a social anisms involved in neuronal development, synaptogenesis,
cognition point of view, the development of joint attention is interneuron function, the mammalian target of rapamycin
closely related to the development of metacognition or theory (mTOR) pathways, GABA receptor function and glutamate
294 R. Tuchman

NMDA receptor function, as well as sodium channel abnor- ID there is a lack of evidence for any substantial risk for ASD in
malities, can cause both epilepsy and ASD.29,37-40 The multiple children with epilepsy.52 ID and ASD commonly coexist and
genes and molecular pathways shared by epilepsy and ASD the early signs of social and nonsocial cognitive function are
indicate a common origin that explains the co-occurrence of difficult to tease apart. Because of this reason, it is important
both disorders, in addition to ID.41 developmentally screen children with epilepsy, for both social
There is evidence suggesting that social cognition, nonsocial and nonsocial-cognitive impairments. In a study of 236
cognition, and epilepsy share not only molecular pathways but children with epilepsy evaluated with multiple instruments
also overlapping anatomical circuitry.13,29 ASD and epilepsy for ASD, approximately 7% had a clinical diagnosis of ASD,
are likely the result of common network dysfunction.42-46 and 12 of these 15 children had other developmental delays or
Malformations in neurogenesis and neuronal migration defects ID.57
have been observed in both disorders. These include cellular In a large community-based cohort of childhood onset
disorganization, heterotopias, and dysplasia.47,31,48 The epilepsy (n ¼ 555), followed prospectively, 5% of children
hypothesis proposes that diverse genetic etiologies of ASD with epilepsy had a diagnosis of ASD. In children with epilepsy
and epilepsy cause a similar dysfunction in interneuronal and IQ above 80, only 2% developed ASD.58 This study found
circuitry, altering the ratio of excitation-inhibition in the that infantile spasms and ID were independent risk factors for
cerebral cortex49,50 and accounting for the coexistence of both the development of ASD.58 Studies on infants with seizures in
disorders.50,51 the first year of life suggest that 35% of those with infantile
The genetic, molecular, and anatomical pathways that lead spasms, go on to develop ASD.59,60 These group of studies
to epilepsy, ASD, and ID are overlapping. Any discussion of the confirm what is observed in clinical practice, that ASD is more
relationship of epilepsy and ASD must account for ID, as social common in children with epilepsy and ID.
and nonsocial cognitive function is inherent part of the A recent meta-analysis on data of 1,449 people with epilepsy
epilepsy and ASD phenotype. The relationship between and 1,295 ASD relatives, found that facial emotional recog-
epilepsy, social cognition, and nonsocial cognition is best nition and theory of mind were poorer in epilepsy compared to
conceptualized as bidirectional and assessing the underlying controls and theory of mind was poorer in those with epilepsy
etiology and pathophysiology accounting for all 3 disorders is than ASD relatives.29 In this study neither age or IQ were
crucial to the development of effective interventions.11 associated with social cognition deficits in people with epilepsy
or in ASD relatives. These findings suggest that there are shared
mechanisms between epilepsy and social-cognitive function,
Clinical Intersection Between independent of the presence of ID. Highlighting the bidirec-
tional relationship of epilepsy and ASD are 2 recent family
ASD and Epilepsy studies, which combined showed that people with epilepsy in
There is a high prevalence of ID in both ASD and epilepsy.52 addition to their siblings and offspring are at increased risk of
Studies on children with ASD indicate that the highest risk of developing ASD. Conversely, people with ASD and their
epilepsy is in those with ID. In a meta-analysis of 24 reports on siblings are at increased risk of developing epilepsy.61,62
patients with ASD and epilepsy the pooled prevalence of A clinical disorder that has attracted much research interest
epilepsy was 21.4% in 1,485 individuals with ASD and ID in assessing the relationship of epilepsy and ASD is TSC.
(intelligence quotient [IQ] o 70) and 8% in 627 persons with Approximatively, 80% of children with TSC develop epilepsy
ASD without ID (IQ 4 70). The highest rate of epilepsy (46%) and the risk for ASD is as high as 50%.63-65 As such, this model
occurred in the group with an IQ o 40.53 In another systemic has been used to look at the effect of early seizures, specifically
review looking at the risk of epilepsy in ASD, the highest infantile spasms, on ASD.66,67 It is suggested that the frequent
pooled estimate was 23.7%, this was found in studies in which seizures in TSC negatively effect early social and nonsocial
the majority had ID and the mean age at follow-up was more cognitive skills and subsequent neurodevelopmental out-
than 12 years.54 In a sample of 5,185 children with ASD, comes.67,68 What these studies found is that by 6 months of
children age 10 or older had 2.35 times the odds of being age infants with TSC differed from controls in having delays in
diagnosed with epilepsy (P ¼ 0.001) and for a one standard the visual mediated social behaviors, specifically in visual
deviation increase in IQ, the odds of having epilepsy decreased tracking and disengagement in attention, but not in language-
by 47% (P ¼ 0.001).55 The investigators found that the average based behaviors such as social babbling and orienting to name.
prevalence of epilepsy was 12% and reached 26% by These early social deficits observed in children with TSC and
adolescence. Language impairments and developmental ASD are similar to the impairments present in children with
regression were not associated with epilepsy after controlling nonsyndromic ASD (without TSC or any other syndrome).69
for IQ. There is strong evidence suggesting that the single most At 12 months infants with TSC with frequent seizures, and
important risk factor for the development of epilepsy in ASD is infantile spasms particularly, were more likely to be diagnosed
the overall cognitive function. Another important finding in with GDD and ASD at later time points.67
this group of studies is that seizures in populations first There is evidence to suggest that ASD in TSC and epilepsy is
diagnosed with ASD are more common after age 10 years an inextricable part of ID and not specific to either disorder.70
and may first present in adolescence or adulthood.56 As discussed in the previous sections, ID is integrally related to
In children with epilepsy the highest risk of developing ASD both ASD and epilepsy and teasing out social-cognitive
is in those with ID. It has been suggested that in the absence of function from nonsocial cognitive function is both difficult
Relationship between ASD and epilepsy 295

and only recently has there been focused attention on this with epilepsy the highest risk of ASD occurs in those with early
issue. Distinguishing the effect of social cognition from that of onset seizures usually starting in the first year of life. The
nonsocial cognition is important in the assessment of infants clinical studies looking at the intersection of the epilepsy-ASD
with epilepsy. Early recognition of social-cognitive deficits may relationship cannot address causality but taken together the
have prognostic implications for treatment. A recent study cumulative evidence suggests a bidirectional relationship
comparing children with TSC and no-ASD, TSC and ASD, between epilepsy and ASD, and more specifically between
nonsyndromic ASD group, and a typical group found that social and nonsocial cognition and epilepsy.
children with TSC and no-ASD, despite having the same
seizure burden as those with TSC and ASD, maintained higher
cognitive skills than the 2 groups with ASD.69 This is an
important observation, as it is possible that both the early
Can Epilepsy or Epileptiform
seizures and the encephalopathy manifesting with ASD are a Discharges Lead to ASD or Can
result of mTOR activation caused by TSC gene mutation ASD Lead to Epilepsy and
and that epilepsy may not significantly impact ASD
outcome in TSC.71 A tenable but as of yet untested hypothesis
Epileptiform Discharges?
is that the early social communication impairments noted in Epileptic encephalopathy is a conceptual term suggesting that
TSC, may effect nonsocial cognition, and that recognition epileptic activity, seizures, or epileptiform discharges, can lead
and treatment of these early signs of social-cognitive epilepsy to cognitive and behavioral impairment above and beyond
could improve prognosis.69 At the very least, studies on what might be expected from the underlying pathology.76 The
epilepsy and ASD in TSC, suggest that treating the early concept is that seizures or epileptiform discharges could cause
developmental signs that put infants at later risk of developing neurodevelopmental problems such as cognitive regression or
ASD may be equally as important as treatment of the ASD. The relative contribution of seizures or epileptic activity
seizures. to cognitive impairment is often difficult to separate from that
Another model that may help us understand the relation- of the underlying etiology.77 The evidence suggests that
ship of epilepsy, ASD and ID is the Dup 15 q syndrome caused children with frequent seizures and epileptiform discharges,
by maternal duplications on chromosome 15q11.2-q13.1 such as those with infantile spasms are more likely to develop
(Dup15q syndrome). This syndrome is considered one of ASD and cognitive impairments. The high incidence of ASD in
the most highly penetrant variants for ID and ASD and is also children with infantile spasms may be linked to a common
associated with epilepsy. A recent large cohort study of 95 underlying etiology as stated earlier.78 Nevertheless, epilepsy
children found that over 60% had epilepsy, identifying multi- or epileptiform discharges, can impact synaptic plasticity,
ple seizure types, both generalized and focal, with infantile cortical connectivity, and alter gene expression, which in turn,
spasms accounting for 42% of seizure types.72 Dup15q causes may predispose the developing brain to social and nonsocial
approximately 3% of ASD and overexpression of the mater- cognitive impairments.79,80 Furthermore treating frequent
nally expressed gene UBE3A is predicted to be the primary seizures or frequent epileptiform electroencephalogram
cause of ASD in dup15q syndrome.73 In a recent study using (EEG) when associated with cognitive regression such as in
in vivo genetics in a mouse model investigators showed that infantile spasms, Landau-Kleffner syndrome (LKS) or in
increasing UBE3A in the nucleus downregulates the glutama- electrical status epilepticus during sleep (ESES) can improve
tergic synapse organizer Cbln1, which is needed for social developmental outcomes.81 Conversely, children with ASD
behaviors in mice.74 Interestingly, the investigators also found may present with frequent seizures and epileptiform discharges
that seizures repress Cbln1, which is involved in social deficits, on the EEG and about 30% of parents of children with ASD
and increase the UBE3A. After removing UBE3A, the seizures report a regression involving loss of a few words and social
did not negatively effect sociability or CBLN1 gene (Cerebel- skills. However, it is important to note that the studies of ASD
lin), however, small increases in UBE3A combined with less and seizures and frequent epileptiform discharges suggest an
frequent seizures did impair sociability in mice. Using viral association and not causality and there is no evidence to date
vector-based chemogenetic activation, the restoration of that seizures or epileptiform discharges cause ASD.82-85,2,86 In
CBLN1 gene in VTA glutamatergic neurons reversed the social addition, the developmental regression observed in children
deficits. This study demonstrated that in certain genetic with ASD is different from the more dramatic cognitive
disorders, seizures may induce pathological changes in gene regression that occurs in disorders such as LKS and ESES.87,88
expression, which may impair social-cognitive skills. In ASD the age of regression is before age 2 years. In LKS and
In summary, clinical studies on the intersection of ASD and ESES, regression usually occurs after age 3 years, except in
epilepsy suggest that ID is a major risk factor accounting for the ESES associated with a structural etiology in which ESES
association of epilepsy in children with ASD and for ASD begins as early as the first year of life. Another difference
occurring in epilepsy. It is important to emphasize that between ASD and LKS or ESES is the severity of regression.
social-cognitive deficits in children with epilepsy are present Children with ASD, usually lose 3-10 words, in addition to a
independently of the coexistence of ID.75 decrease in social engagement. This contrasts with the more
The temporal relationship between ASD and epilepsy is dramatic loss of language skills that occurs in LKS and the
complex. Children with ASD are more likely to develop cognitive deficits that develop in children with ESES. The EEG
seizures in the second and third decade of life. In children abnormalities associated with ASD usually consist of
296 R. Tuchman

infrequent centro-temporal spikes, as opposed to the more Epilepsy Social Cognitive

dramatic “electrical status epilepticus during slow wave sleep,” ETIOLOGY Epileptiform
Impairments
Developmental
observed in patients with LKS and ESES.87 ASD can also share Discharges Outcome

a genetic etiology with disorders such as LKS and ESES.89-93

There are now numerous studies that clearly demonstrate Figure 2 The etiology causes the epilepsy and the epileptiform
shared mechanisms between ASD, ID, and the “developmental discharges, which than leads to the social-cognitive impairments
epilepsies.”94 and developmental outcome of ASD.

further detrimental neurodevelopmental outcome even if the

When Epilepsy and ASD Coexist: seizures are successfully treated. Interventions, in the model
What Are we Treating? depicted in Figure 3, would focus on treating the etiologies that
The most effective treatments for ASD are based on behavioral could lead to both epilepsy and ASD and targeting both the
and educational interventions. This is achieved through seizures and the social and nonsocial cognitive deficits.
enrichment of the environment, so as to provide the child Most of the identified etiologies that account for the co-
with ASD a structured environment to learn the rules of social occurrence of epilepsy and ASD are genetic. At the present
engagement.95,96 Medications to treat ASD can be effective for time-specific treatment for most of these genetic abnormalities
ameliorating ASD associated symptoms such as irritability but is not available. In some genetic epilepsies associated with ASD,
have limited effects on neurodevelopmental outcomes, and treatment directed to the specific etiology could improve
specifically are not effective for improving social-cognitive epilepsy and developmental outcomes.35,86,85 An example is
skills over the long term. the use of mTORc inhibitors in TSC and PTEN mutations.97-99
In epilepsy, the focus of treatment has been antiepileptic In TSC, there is some evidence that the early use of vigabratin
drugs (AEDs) and surgical approaches to treat the seizures and for infantile spasms may improve ASD symptoms and neuro-
less attention has been paid to behavioral and educational developmental outcomes.100-103
interventions that along with AEDs could improve develop- Identification of common genetic pathways leading to ASD
mental outcomes. Present AEDs and surgical interventions in and epilepsy may lead to treatments that have potential benefit
epilepsy, are effective for seizure reduction but neurodevelop- for both disorders. A rare example is branched chain ketoacid
mental outcomes, even when seizure freedom is achieved, are dehydrogenase kinase mutation, which can lead to ASD, ID,
highly variable. and epilepsy and is a potentially treatable syndrome.104
In considering potential points of intervention in children Another example that has been identified is in a dup(15)
with ASD and epilepsy, we need to evaluate the etiology, autism subcohort with microcephaly, very early onset of
the role of the seizures and epileptiform activity, and the effect seizures, a high percentage of intractable seizures, and a high
of early social-cognitive deficits on neurodevelopmental prevalence of sudden unexpected death in epilepsy. A high
outcomes. In Figure 1, we consider a common etiology for percentage of neurons with accumulation of α-secretase
seizures, interictal epileptiform discharges, and the social and product, is found in these children, suggesting a functional
nonsocial cognitive impairment. In Figure 2, we assume a link between ASD, epilepsy and alterations of amyloid beta
specific etiology leading to epilepsy or interictal epileptiform precursor protein processing.105 This suggests that at least in
discharges which in turn leads to poor neurodevelopmental some cases, ASD and epilepsy may be potentially amenable to
outcomes, including ASD. Figure 2 represents the previous
discussion on the effect of epilepsy or epileptiform discharges
ETIOLOGY
on ASD. In Figure 3, we consider an etiology, which can lead to
either seizures, epileptiform discharges, ASD or both. In this
model, the seizures could have a detrimental effect on develop-
ment leading to symptoms of ASD, and the ASD could lead to
Cognition: Social
Epilepsy
and Non-Social
Cognition
Non-Social

Social
Cognition Figure 3 The etiology leads to either the epilepsy and to the epilepti-
ETIOLOGY form discharges or the social and nonsocial cognitive impairments.
Epilepsy The seizures and epileptiform discharges have an added negative effect
on social and nonsocial cognitive development. The cognitive deficits
Epileptiform can also impact the epilepsy, at least at the level of neurodevelop-
discharges mental outcome and in animal models (see text), environmental
enrichment may reduce seizures and delay epileptogenesis. This later
Figure 1 The etiology is primarily responsible for social and nonsocial point is hypothetical and clinical studies in children with epilepsy and
cognition, epilepsy and epileptiform discharges. ASD where both disorders are targeted with interventions are needed.
Relationship between ASD and epilepsy 297

pharmacological interventions, such as the use of secretase improve nonsocial cognitive function, adaptive and social
inhibitors.106 These findings illustrate the importance of behaviors, and these gains are maintained for at least 2-years
conducting extensive genetic workup in all children with postintervention.118-120 Early interventions for ASD delivered
epilepsy, ASD, and ID. by parents for children at familial risk for developing ASD,
Although etiology is the major determinant of neurodeve- reduced the overall severity of prodromal ASD symptoms and
lopmental outcomes in children with epilepsy and ASD, there enhanced social communication between parent and child.121
continues to be considerable interest in the study of whether These types of interventions have not been studied in children
treatment of epilepsy and epileptiform discharges may have a with epilepsy at risk for ASD. There is some emerging evidence
beneficial effect on developmental outcomes. One recent study that they could potentially not only have a positive effect on the
has shown that in children with medically resistant epilepsy social behaviors of ASD but may also effect seizures. This
and with a structural etiology, interictal epileptiform discharges evidence comes from animal models showing that environ-
have an independent association with cognitive impair- mental enrichment reduces spontaneous seizures, delays
ment.107 From a treatment perspective a small study on 11 limbic epileptogenesis, and may be helpful in depression in a
patients with ESES and 21 controls investigating the effects of chronic temporal lobe epilepsy model.122-124 Research is
hemispherotomy on language development found that chil- needed to explore the hypothesis of whether interventions
dren with remission of ESES postsurgery had significant could enhance social cognition by effecting gene expression,
increase in language skills, which could not be explained by improving developmental outcomes, and reducing seizure
seizure freedom alone as seizure free children without pre- burden.
operative ESES showed less improvement after surgery.108 In Treating the seizures is necessary but may not be sufficient to
conclusion, this data suggest that treatment of the interictal maximize neurodevelopmental outcomes.125 The studies dis-
epileptiform discharges may have a positive effect on neuro- cussed above highlight the complex interplay between seizures
developmental outcome. This still remains a controversial issue and social cognition and suggest that the treatment of the child
as highlighted in a study of LKS where it was found that with ASD and epilepsy needs to target not only seizure
multiple subpial transection did not provide any additional reduction but social-cognitive development as well. Social-
improvement as compared to a control group with LKS that cognitive development and epileptogenesis may share genetic
did not have surgery.109 In addition, a study on a cohort of 44 and molecular mechanisms despite being two very different
children with infantile spasms, 23% developed ASD, and processes.79,126 Interventions that target both processes, the
although the investigators found that they could identify social-cognitive deficits preceding ASD and epileptogenesis are
children with ASD early on, effective early treatment of the likely the best hope for maximizing neurodevelopmental
infantile spasms with vigabratin did not prevent ASD.110 outcomes in children with ASD.
In a recent prospective longitudinal study from the TSC
Autism Center of Excellence Network it was found that early
seizure onset in infants with TSC negatively effects neuro-
Conclusion
development but that improved seizure control did not In answering the question, what is the relationship of ASD to
influence developmental outcomes. Interestingly, achieving epilepsy and epilepsy to ASD, several major points emerge.
better seizure control did not improve developmental out- First, the relationship between epilepsy and ASD, is at the core,
comes, suggesting that early onset seizures may predict a an interaction between social cognition, nonsocial cognition
negative treatment response.67 On the other hand a small and seizures. Second, the ASD-epilepsy connection is dynamic
study of 10 children with TSC demonstrated that early and bidirectional closely linked to ID. Third, epilepsy, ASD,
treatment of seizures with vigabratin prevented the develop- and ID share molecular, structural, and functional neural
ment of ASD.100 A similar study on 45 infants with TSC treated networks. Fourth, understanding the shared mechanisms that
with vigabatrin found that controlling the EEG abnormalities lead to a child having both epilepsy and ASD should allow the
before the seizures developed improved developmental out- development of novel intervention with the potential to
comes.103 Although the beneficial effects on developmental prevent or ameliorate epilepsy and the social-cognitive deficits
outcomes in the latter two studies may reflect early seizure that define ASD. Finally, there has been a paradigm shift in our
control or suppression of epileptiform discharges before thinking of epilepsy as it relates as it relates to ASD and social
seizures, it is also possible that vigabratin’s role in inhibiting cognition, whereas traditionally the sole focus was on treating
mTOR overactivation may have an effect on glutamatergic the seizures, it is now evident that controlling the seizures is
mechanisms important in brain development, synaptic plasti- necessary but not sufficient to maximize neurodevelopmental
city, and in social and nonsocial cognition, accounting for both outcomes.
seizure suppression and amelioration of social and nonsocial The relationship between epilepsy and ASD highlights the
cognitive deficits.71,111–113 effects of social cognition on neurodevelopment. As we move
Interventions for social cognition in children with forward in our understanding of the connection between
epilepsy and ASD have been understudied.114,115 There is epilepsy and ASD we need to design studies looking at the
accumulating evidence that interventions for social-cognitive effect of combined treatments targeting seizures and social
skills may impact outcomes in ASD and that they can be cognition. In the meantime, early recognition and intervention
instituted before the diagnosis of ASD, that is in children at risk of social-cognitive deficits should be part of the comprehensive
for ASD.116,117 Intervention targeting social cognition can management plan of all children with epilepsy.
298 R. Tuchman

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