Autism spectrum disorders and epilepsy: Moving towards [615398]

Review article
Autism spectrum disorders and epilepsy: Moving towards
a comprehensive approach to treatment
Roberto Tuchmana,b,*, Michael Alessandric, Michael Cuccarod
aDepartment of Neurology, Miami Children’s Hospital, Dan Marino Center, Weston, FL, USA
bUniversity of Miami, Department of Neurology, Miami, FL, USA
cDepartment of Psychology, University of Miami, Coral Gables, FL, USA
dDepartment of Human Genomics, Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA
Received 1 April 2010; received in revised form 15 May 2010; accepted 17 May 2010
Abstract
The biological and phenotypic heterogeneity of children with autism spectrum disorders (ASD) and epilepsy presents a significant
challenge to the development of effective treatment protocols. There is no single treatment or treatment protocol for children with ASD
or epilepsy. Children with co-occurring ASD and epilepsy should undergo a comprehensive assessment that includes investigation ofunderlying biological etiologies as well assessment of cognitive, language, affective, social and behavioral function prior to initiating
treatment. The comprehensive treatment of children with ASD is based on a combination of therapeutic psychosocial interventions
in combination with pharmacological agents. A process-oriented approach to assessment and intervention allows careful analysis ofthe child’s response to treatment such that treatment protocols may be revised secondary to any changes in developmental trajectory
of the child with ASD and epilepsy. The possibility of developing pharmacological interventions that target both ASD and epilepsy
awaits definitive evidence. The best hope for good developmental outcomes in children with ASD and epilepsy is early recognitionand comprehensive treatment of both the ASD and epilepsy./C2112010 Elsevier B.V. All rights reserved.
Keywords: Epilepsy; EEG; Autism; Epileptic encephalopathy; Treatment
1. Introduction
Autism spectrum disorder (ASD) is a broad classifi-
cation that includes a heterogeneous group of individu-als with behaviorally defined impairments in reciprocalsocial interaction, verbal and non-verbal communica-
tion, and restricted and repetitive behaviors. The ASD
category includes those with autistic disorder, pervasivedevelopmental disorder not otherwise specified orAsperger syndrome. It excludes two other categoriesincluded in the Diagnostic and Statistical Manual of
Mental Disorders 4th Edition Text Revision (DSMIV-TR) [1]and the 10th Edition of the International
Classification of Diseases (ICD 10), Rett disorder andchildhood disintegrative disorder. Epilepsy is anotherbroad diagnostic category and is defined as having more
than one seizure. Seizures are the most dramatic aspect
of epilepsy although recent definitions of epilepsy haveemphasized the neurologic, cognitive, psychological,and social consequences of this group of disorders [2].
Classification systems for seizures [3]and for epilepsy
[4]have been developed and are academically useful
but how best to classify seizures and define epilepsyremains an evolving and controversial issue [5].
The prevalence of epilepsy in the ASD population is
estimated to be approximately 30% although this number
0387-7604/$ – see front matter /C2112010 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2010.05.007*Corresponding author. Address: Miami Children’s Hospital, Dan
Marino Center, 2900 South Commerce Parkway, Weston, FL, USA.
Tel.: +1 954 385 6202.
E-mail addresses: roberto.tuchman@gmail.com ,tuchman@att.net
(R. Tuchman).www.elsevier.com/locate/braindevBrain & Development 32 (2010) 719–730

is highly variable depending on the study sample [6].
While the prevalence of ASD in children with epilepsyhas been studied less, Clark and colleagues [7]found that
approximately 30% of children in a tertiary epilepsy clinicmet criteria for ASD. Clearly, the association of ASD andepilepsy is higher than one would expect by chance and
the co-occurrence of ASD and epilepsy negatively
impacts developmental outcomes and quality of life [8].
In children with epilepsy, younger age at seizure
onset, cognitive impairment, temporal or frontal lobeonset of seizures, and intractable epilepsy are associatedwith an increased likelihood of co-existing social-com-munication and behavioral disorders [9]. In children
with ASD, cognitive and motor impairments, severity
of receptive language deficits, and genetic and molecular
abnormalities are associated with an increased preva-lence of epilepsy [10]. In some children with co-occur-
ring ASD and epilepsy there appears to be a commonetiology and pathogenesis. However, our understandingof the pathophysiology of co-occurring ASD and epi-lepsy is still limited. While the ASD and epilepsy catego-ries are useful and practical for classification purposes
they are mainly descriptive and do not reflect singular
entities with uniform etiologies [11,12] . It follows that
there is no one single treatment or treatment protocolfor children with ASD or epilepsy.
How often a common cause accounts for the co-
occurrence of ASD and epilepsy is an interesting butas yet unanswered question. The answer to this questionand an understanding of the pathogenesis common to
both ASD and epilepsy will provide an avenue for novel
therapeutics. At present, the known biological and phe-notypic heterogeneity of children with ASD–epilepsyphenotypes presents a significant challenge to the devel-opment of treatment protocols. Throughout this reviewof intervention options we highlight therapeutic strate-gies most likely to improve developmental outcomesfor children with ASD and epilepsy.
2. Children with ASD who develop epilepsy
The aim of treatment in children with epilepsy is to
effectively eliminate seizures without compromising cog-nitive and behavioral functions [13]. This aim applies
equally to the treatment of epilepsy in children with anestablished diagnosis of ASD [14,15] . Pharmacological
interventions for epilepsy that reduce and eliminate sei-
zures have been developed [16]and these medications
are effective in reducing or eliminating seizures in chil-dren with ASD and epilepsy. As in epilepsy, seizuretype, EEG findings, and the presenting clinical syn-drome guide treatment in children with autism and epi-lepsy. While managing seizures is crucial to allconditions in which epilepsy is present, treatment of
the child with ASD and epilepsy raises additional layers
of complexity and accompanying considerations.Cognitive and language impairments, mood disor-
ders, and a range of social and behavioral problemscommonly co-exist with epilepsy and may impact out-come as much as or perhaps even more than the seizuresthemselves [9]. At present, our knowledge of effective
interventions for the cognitive, neuropsychiatric, and
behavioral aspects of epilepsy is limited [17–19] .I n
ASD, like epilepsy, there are a number of co-existingdisorders. These include various genetic disorders [20],
metabolic disorders [21], sleep disorders [22–27] and
medical problems such as gastrointestinal dysfunction[28]. In addition, the mitochondrial dysfunction is
increasingly being recognized in children with ASD[29,30] and mitochondrial function is more common
than appreciated among children with childhood epilep-
sies, including a number of the epileptic syndromes asso-ciated with autism [31]. While a range of interventions
have been proposed for some of these co-existing condi-tions in ASD, there remains no clear prescriptiveapproach and limited evidence relative to treatmentefficacy.
Co-existing conditions common to both epilepsy and
ASD as separate disorders challenge both diagnostic
and therapeutic strategies when both disorders co-occurin the same child. The heterogeneity of clinical symp-toms in children with ASD and epilepsy highlights theimportance of a comprehensive assessment that includesinvestigation of underlying biological etiologies as wellassessment of cognitive, language, affective, social andbehavioral function prior to initiating treatment and
throughout the intervention process. This approach to
assessment and intervention allows careful analysis ofthe child’s response to treatment such that treatmentprotocols may be revised secondary to any changes indevelopmental trajectory of the child with ASD andepilepsy.
2.1. Comprehensive treatment approach
By definition, children with ASD present with deficits
across a broad range of developmental and behavioraldomains. These may include delayed or disorderedsocial-communication, behavioral responses, and intel-lectual and adaptive functioning. As such, a comprehen-sive treatment approach is warranted to effectivelytarget the presenting clinical symptoms, including those
central to the disorder along with associated features,
both of which negatively impact overall functioning.Currently, the comprehensive treatment of children withASD is based on a combination of therapeutic psycho-social interventions in combination with pharmacologi-cal agents. This type of approach has recently beenreviewed [32]. Pharmacological interventions for chil-
dren with ASD are primarily used to treat the co-exist-
ing affective and behavioral disorders or to target
specific symptoms such as inattention, hyperactivity,720 R. Tuchman et al. / Brain & Development 32 (2010) 719–730

impulsivity, repetitive behaviors, aggressiveness or irri-
tability [33–36] . Pharmacological agents have not been
effective at treating the core symptoms of ASD [37]
nor have they been observed to change the developmen-tal outcomes of children with ASD [38,39] .
2.2. Psychosocial interventions
The clinical utility of structured, highly engaged and
intensive, individualized treatments for those affected byASD [40]is now well accepted. The most common inter-
ventions for individuals with autism spectrum disordersare psychosocial, not medical, interventions that targetthe core social-communication deficits and prominent
behavioral disturbances that interfere with the acquisi-
tion of functional skills [41–43] . An understanding of
the role these interventions play in the comprehensivemanagement of the child with ASD and epilepsy isessential. The philosophies guiding the varied psychoso-cial approaches are distinct, from relationship-basedapproaches that focus on underlying developmental pro-cesses to applied behavior analytic approaches that
focus on teaching behaviors and skills through environ-
mental manipulations.
The particular treatment approach, the specific treat-
ment objectives, the intervention setting, and the mem-bers of the treatment team should all be carefullyselected based on child developmental level and chrono-logical age, family resources and available supports, andthe presence/absence of co-morbidities. Developmental
status, along with chronological age of the child, is of
particular importance in decision-making regardingtreatment. Treatments that are known to be effectiveat remediating some deficits related to ASD in preschoolor school-age children are not likely to be effective orappropriate in treating those at other age levels. Forexample, Zwaigenbaum and colleagues review clinicalassessment and treatment practice guidelines for tod-
dlers with suspected ASD given their unique develop-
mental characteristics [44]. This review highlights
important considerations one must make when treatingthe very young child with either a confirmed or a sus-pected diagnosis of ASD, including the context andmanner in which toddlers learn social responses andthe critical role of parental responsivity and sensitivityto early learning. Zwaigenbaum and colleagues recom-
mend interventions that focus on natural learning envi-
ronments, sensory-motor based learning opportunities,and, perhaps most importantly, child-initiated learning.This contrasts dramatically with some of the existingbehaviorally-based treatment approaches for preschooland school-age children with autism spectrum disorderswhich may be clinic- or school-based, somewhat pre-scriptive, and teacher- or therapist-directed.
One particular challenge that compromises response
to treatment in ASD is the presence of intellectual dis-ability. Recent epidemiological studies suggest that
approximately 40–60% of children with ASD, dependingon the subgroups of ASD included, have some degree ofintellectual disability [45,46] . Epilepsy in children with
ASD is similarly associated with degree of intellectualimpairment [47]. While psychosocial interventions that
are behavioral and communication-focused have benefi-
cial effects in children with ASD [48], the degree of
improvement is likely modulated by level of intellectualfunctioning of the child and other factors [49].
While early treatment outcome studies demonstrated
significant cognitive, language and adaptive functioninggains in children with ASD secondary to intensivebehavioral interventions, the impact of such interven-
tion on the core social-communication disturbance
remained unclear [50–53] . More recently, there is grow-
ing evidence to suggest that methods for modifyingsocial-communication behaviors in children with ASDcan be effective [54]. Toward this end, encouraging, yet
preliminary, findings are now being reported from anemerging body of literature on behaviorally-based jointattention interventions in children greater than
36 months of age [40,55] . Joint attention refers to the
capacity of individuals to coordinate attention with asocial partner in relation to some object or event. Thisskill begins to emerge by at least 6 months of age andappears to be critical to the establishment of moresophisticated social-communication [56]. Joint attention
behaviors, in fact, serve important social functions andare crucial prerequisites to the development of social
cognition and language [57–59] . Although individual
differences exist, joint attention impairments are amongthe earliest and most consistently identified social-com-munication deficits in children with ASD. Joint atten-tion also may represent one of the earliest modifiableskills in young children on a developmental trajectorytoward ASD, and if successfully modified may serve asa pivotal skill in the development of more typical lan-
guage and social cognitive outcomes [60]. Therefore, it
is plausible that utilization of techniques to enhancejoint attention early in the course of seizures or priorto the emergence of full-blown ASD may positivelyimpact the developmental trajectories of children withASD and epilepsy.
2.3. Antiepileptic drugs
Antiepileptic drugs (AEDs) are administered widely
to children with ASD with and without epilepsy [61].
The psychotropic mechanism of action of several AEDsis now well established and there is support for their rolein treating children with epilepsy and co-existing moodand behavioral disorders [62–64] . At present, no ran-
domized controlled trials or large clinical studies have
tested the effects of these anticonvulsants in well-defined
populations of children with ASD and epilepsy to guideR. Tuchman et al. / Brain & Development 32 (2010) 719–730 721

treatment of a child with ASD and epilepsy. Most of the
published work has consisted of clinical reports thatdescribe response to various medications (valproic acid,lamotrigine, and levetiracetam) and highlight limitationsof pharmacological interventions in the child with aut-ism and epilepsy.
Valproic acid is one of the most commonly reported
medications used in the treatment of ASD and epilepsy.Several clinical reports note improvement in childrenwith either ASD with seizures or ASD without clinicalseizures but with EEG epileptiform abnormalities trea-ted with valproic acid [65–67] . An open trial in 14 indi-
viduals using divalproex sodium found improvement incore symptoms of autism and associated affective insta-
bility, impulsivity, and aggression, only in those children
with autism and an abnormal EEG or seizure history[68]. Another widely used AED is lamotrigine, an anti-
convulsant with a beneficial psychotropic profile. In astudy of lamotrigine for children with intractable epi-lepsy, a subset of 13 children with co-occurring autismshowed a decrease in ”autism symptoms ”without a con-
comitant decrease in seizures, suggesting a specific ben-
efit of lamotrigine in autism [69]. A subsequent double-
blind placebo control trial of lamotrigine in 28 childrenwith autism without seizures found no significant benefitacross multiple behavioral indicators; parents, however,reported a beneficial effect of lamotrigine [70].
The findings of whether AEDs have positive psycho-
tropic effects on children with ASD with or without epi-lepsy are equivocal. For example in an open label study
of levetiracetam in 10 children with ASD without epi-
lepsy, positive effects were noted on measures of hyper-activity, impulsivity, mood instability, and aggression[71]. However, a second study of levetiracetam in 20
children with ASD and no seizures found no positiveeffects on behavior [72]. Recently an open label trial of
levetiracetam in six children without ASD or epilepsybut with “subclinical spikes ”in association with neuro-
psychological impairments in attention and learning
found improvements with concomitant spike suppres-sion in four of the six children [73]. Other potential
interventions that have been used in epilepsy such asvagal nerve stimulation and the ketogenic diet have beentried in children with both epilepsy and ASD with mixedresults [74–78] .
Despite our current understanding of the neurobiol-
ogy of ASD and the success of pharmacotherapy for dis-
ruptive behaviors, effective pharmacotherapy for thecore social and language impairments of ASD remainselusive [79]. Furthermore, our understanding of the
use of AEDs in ASD and epilepsy is limited as thereare few studies that have directly studied this group ofchildren. In addition, clinical heterogeneity and numer-ous co-existing conditions found in both ASD and epi-
lepsy challenge our ability to measure effectiveness,
particularly developmental outcomes. The few studiesthat have been conducted have included small numbers
of children, were based on short periods of observation,relied on incomplete diagnostic measures of either ASDor epilepsy, and measured efficacy in a limited fashion.
3. Children with epilepsy who develop ASD
In children with epilepsy the highest risk for developing
ASD is in those with seizures in the first year of life [80].
Approximately 40% of all epilepsies occurring duringthe first 3 years of life fit the definition of epileptic enceph-alopathies [11]. Epileptic encephalopathies are defined as
“a condition in which the epileptiform abnormalities
themselves are believed to contribute to the progressive
disturbance in cerebral function ”[81]. The epileptic
encephalopathies begin early in life and include disorderssuch as early myoclonic encephalopathy, West syndrome,Dravet syndrome, myoclonic status in nonprogressiveencephalopathies, Lennox–Gastaut syndrome, Landau–Kleffner syndrome (LKS), and epilepsy with continuousspike-waves during slow-wave sleep (CSWS). As a group,the epileptic encephalopathies are associated with regres-
sion or slowing of cognitive, language, or behavioral
development; the hypothesis is that the seizures or theinterictal epileptiform activity are responsible for thedeterioration [82–84] .
3.1. Medical treatments of epileptic encephalopathies
Epileptic encephalopathies are associated with a high
risk of cognitive, language, social and behavioral deteri-
oration, and aggressive early therapy is recommended[85]. Interventions commonly used in this group of chil-
dren include AEDs, steroids and ACTH, immunoglobu-lins, vagal nerve stimulation, ketogenic diet, andepilepsy surgery [86–90] . Among these epileptic enceph-
alopathies, West syndrome or infantile spasms (IS),LKS, and CSWS are most commonly associated with
an ASD phenotype [91]. However, it should be noted
that the ASD phenotype might not be exclusive to thesethree encephalopathies; the ASD phenotype may beunder-recognized or under-investigated in other epilep-tic encephalopathies. For instance, Dravet syndrome[92] is a genetically determined infantile epileptic
encephalopathy mainly caused by de novo mutationsin the SCN1A gene. Recently a sporadic infantile epilep-
tic encephalopathy that resembles Dravet syndrome has
been tied to mutations in PCDH19 [93]. These genes
associated with Dravet syndrome appear to have rele-vance to ASD. Specifically, a susceptibility locus forASD has been found on chromosome 2 in the vicinityof the epilepsy involved genes SCN1A and SCN2A [94]
while PCDH10 on chromosome 4 has been linked to
ASD in families with shared ancestry
[95]. These results
hint strongly at possible shared molecular underpin-
nings between ASD and this epileptic encephalopathy.722 R. Tuchman et al. / Brain & Development 32 (2010) 719–730

The association of infantile spasms (IS) and ASD is
well recognized [96,97] ; in children with IS the preva-
lence of ASD is as high as 35% depending on the severityof intellectual disability [98]. In addition, there appears
to be a heightened risk of ASD in the presence of symp-tomatic epilepsy as ASD is most likely in children with
IS resulting from one or more identifiable structural
lesions of the brain [99]. Further, in children with IS,
EEG epileptiform activity – particularly bilateral frontalEEG discharges and persistence of hypsarrhythmia –contributes to the development of the ASD phenotype[100]. One study suggested that the use of vigabratin
in children with IS and tuberous sclerosis may improvecognitive outcome and prevent the development of the
ASD phenotype [101]. Although early and aggressive
medical and surgical treatments for IS are advocated,there is no clear evidence that current intervention strat-egies improve developmental, cognitive or social com-municative outcomes [102]. Finally, it may be that IS
etiology is the most reliable predictor of developmentaloutcome [103].
The two other epileptic encephalopathies that are
commonly associated with ASD are LKS and CSWS
[104]. The overlap of the LKS and CSWS behavioral
phenotypes with ASD has led to diagnostic confusionand controversy [105–109] . In LKS, corticosteroid ther-
apy has yielded improvements in language [110–114] .I n
addition, a number of interventions including nicardi-pine [115] vigabratin [116,117] , sulthiame and clobazam
[118], levetiracetam [119], diazepam [120] immunoglobu-
lins and ketogenic diet [90,121–123] have been associ-
ated with improvements in behavioral and languagefunctioning in children with LKS. In children with elec-trical status epilepticus during slow-wave sleep (ESES),exclusive of LKS, the most effective treatment was ste-roids which successfully abated the EEG discharges in65% of children; other treatments such as immunoglob-ulins and AEDs were successful in less than 50% of cases
[124]. There are other reports in which drugs or drug
combinations have been successful at abating EEG dis-charges in children with LKS with or without ESES,however there is no agreement on which medication touse, when to start one particular treatment over another,and what to use as an endpoint for success [13,85] . Gen-
erally, oral prednisone, high doses of intravenous pulsecorticosteroids, and corticotropin (adrenocorticotropic
hormone) have been the most effective treatments in
LKS and CSWS [120].
3.2. Surgical experience
Multiple subpial transection (MST) has been the
most common neurosurgical treatment for LKS withmultiple reports suggesting post-operative improvement
in language function [125–129] . Of interest, approxi-
mately 20–40% of epilepsy surgery candidates have anASD phenotype [130–132] . The subgroup of children
undergoing epilepsy surgery is an important group thatmay provide some perspective on treatment effects andoutcome. In children with ASD with and without intrac-table seizures that have undergone epilepsy surgery,there are reports of transient behavioral improvements;
however core deficits in social-communication function-
ing remain, as do other affective and social emotionalissues [131,133–136] . It is clear that early aggressive
treatment with drugs or surgery to treat the seizures orthe epileptiform activity in children with epilepticencephalopathies is warranted. What is less clear iswhether successful surgical treatment of seizures or epi-leptiform discharge abatement improves developmental
trajectories of these children [137–139] . Intellectual
capacity influences response to intervention in childrenwith ASD and epilepsy, and current medical and surgi-cal interventions do not appear to dramatically alterintellectual ability [132].
4. Controversies in treatment: regression and epileptiform
EEG
There continues to be debate whether epilepsy or the
epileptiform EEG could be a causal factor in the devel-opment of the ASD phenotype and whether treatment,medical or surgical, can prevent or reverse the cognitiveand behavioral manifestations [140]. What we can say is
that children with epileptic encephalopathies, especiallythose with seizures in the first 3 years of life, are at high
risk for the development of ASD. What is controversial
is whether epileptiform activity can trigger regression oflanguage and social-communication that occurs inapproximately one third of children with ASD [141].
In addition current pharmacological treatments for chil-dren with both ASD and epilepsy be they medical orsurgical, may be effective at treating the seizures butare rarely effective in treating the cognitive, language,
and social function.
4.1. Autistic regression with epilepsy or epileptiform EEG
Two childhood disorders associated with regression
and severe intellectual disability and both historicallyassociated to ASD are Rett syndrome and childhooddisintegrative disorder. Childhood disintegrative disor-
der is characterized by late-onset autistic and cognitive
regression that can include motor regression and lossof bowel and bladder use, usually occurring after age 3[142–144] . The prevalence of epilepsy in disintegrative
disorder has been reported to be as high as 77%
[145]
and EEG abnormalities are significantly more commonin the histories of those with disintegrative disorder thanthose with ASD [146]. Some of these children may over-
lap with those with epilepsy and CSWS [147]. Rett syn-
drome is also associated with a higher prevalence ofR. Tuchman et al. / Brain & Development 32 (2010) 719–730 723

epilepsy than in children with ASD and severe intellec-
tual disability [148]. To what extent the high rate of sei-
zures in these groups is secondary to the severe cognitiveimpairment present in both Rett and disintegrative dis-order or what influence other specific variables such asmetabolic or molecular factors (i.e., the role of MECP2 )
have in the development of seizures remains unknown.
The developmental trajectory in approximately 30%
of children with ASD is characterized by a regressionof the few words acquired and a loss of non-verbal com-munication skills usually occurring prior to 24 monthsof age [149–155] . This regression has been termed autis-
tic regression. The relationship of autistic regression toepilepsy or to an epileptiform EEG without seizures
remains controversial with some studies reporting
higher rates of epilepsy in children with ASD and regres-sion [156,157] and others showing no relationship
between ASD, epilepsy and regression [155,158] .A
recent study found that children with autistic regressionhad more disrupted sleep as compared to those with aut-ism without regression and were more likely to have epi-lepsy [159]. In addition, Giannotti and colleagues found
that epileptiform activity did not differ among those
with and without regression except that those with autis-tic regression were more likely than those withoutregression to have more “frequent epileptiform EEGs ”.
The differences between children with autistic regres-
sion and those with primary language regression, asoccurs in LKS, were highlighted in a multicenter studywhich found seizures to be more common in children
who regressed in language after the age of 3 years and
that children with seizures were less likely to have autis-tic regression [160]. A study that compared the over-
night EEG results of children with language regressionto those of children with autistic regression found thatchildren with isolated language regression were morelikely to have epileptiform discharges, particularly focalspikes, than those with a more global autistic regression
affecting both verbal and non-verbal communication
skills [161]. Furthermore McVicar and colleagues
showed that electrical status epilepticus during slow-wave sleep (ESES), which is the EEG pattern associatedwith LKS and other epileptic encephalopathies of sleep,is almost exclusively found in those with isolated lan-guage regression [161].
4.2. Epilepsy and epileptiform EEG in ASD: when to treat
There is research suggesting that interictal epilepti-
form activity can impair brain function [162–164] and
children with ASD with an epileptiform EEG and noseizures are commonly identified [136,165,166] . How-
ever, a review of the literature on ASD, epilepsy and epi-leptiform EEGs pointed out that of 11 prospective
studies (single cases or small groups) in which the
authors assumed that the ASD was of epileptic origin,only 8 of 24 children had an ASD that could be related
causally to the epilepsy [167]. There are rare children
with ASD and epilepsy or ASD and an epileptiformEEG that are progressing well and then have a changein behavior or sudden deterioration in language, social,or cognitive skills that develop into a clinical picture
suggestive of LKS or CSWS in association with an
ESES pattern on the EEG.
Roulet-Perez and Deonna [167] have described sev-
eral children where a change in developmental trajectoryrequires re-assessment of intervention strategies. Theseinvestigators highlighted two children in the McVicaret al. study that had a late regression with EEG featuresof LKS “superimposed on a previous diagnosis of
autism ”[161]. Canitano et al. [168] in their study of 46
children with ASD reported one child in whom autisticregression at age 2 years was closely associated with cen-tro-temporal spikes on the EEG without seizures. Inaddition a recent exceptional case report of a 7 yearold girl meeting criteria for LKS and for autistic regres-sion secondary to a right temporal ganglioglioma pointsto the importance of staying vigilant for changes in
behavior, language or social function in all children with
ASD and epilepsy; in this case, elimination of seizurespost resection with improvement of language and socialskills almost 2 years post surgery were documented[169]. These examples are rare and require close correla-
tion of the epilepsy and EEG with language, cognitiveand behavioral measures [170].
The differences between children with ASD, regres-
sion and an epileptiform EEG with or without seizures
and those with epileptic encephalopathies such as LKSand CSWS have been extensively reviewed [141].
Although the behavioral phenotypes of CSWS, LKS,and autistic regression overlap, the differences in ageof regression, degree and type of regression, and fre-quency of epilepsy and EEG abnormalities suggest thatthese are distinct phenotypes. The concept of ASD as an
epileptic encephalopathy is neither correct nor useful,
and children with autistic regression in general haveinfrequent isolated epileptiform activity that is rarelyassociated with ESES, the EEG pattern common toboth LKS and CSWS [171]. Furthermore, there is no
evidence to suggest that treatment of the interictal spikeson the EEG has a beneficial effect on the social commu-nicative impairments of children with ASD [172].
As the clinical value of an EEG in a child with ASD
without clinical convulsions is unclear, the determina-tion of when or whether to consider performing anEEG in children with ASD is controversial [173,174] .
It has been suggested that an EEG needs to be consid-ered when there is clinically significant loss of socialand communicative functions and there is a clinical sus-picion that abnormal electrical activity may be contrib-
uting to the regression [175]. However, the most recent
review that attempted to provide evidence-based guide-724 R. Tuchman et al. / Brain & Development 32 (2010) 719–730

lines for performing an EEG on children with autism
found that there was insufficient evidence to recommendfor or against the routine use of screening EEGs in chil-dren with ASD [176]. A high degree of clinical suspicion
for epilepsy needs to be maintained for any child withlanguage or autistic regression at any age, but especially
in those over the age of three with a regression in lan-
guage. An individualized approach dependent on clini-cal symptoms and developmental progress is neededfor determining the need for investigation with pro-longed EEG studies.
If epileptiform activity is found in a child with ASD
without seizures, interpretation of these findings andany intervention or action needs to done within the clin-
ical context of the individual child’s symptoms and
developmental trajectory. If the EEG shows epilepti-form activity that can be correlated directly to eitherregression of a particular skill especially if the EEG ismarkedly increased in sleep then the intervention strate-gies used for epileptic encephalopathies should be con-sidered. Re-assessment of treatment response andmonitoring for side effects of the medications used needs
to be done on an ongoing regular basis.
The other scenario is the child with ASD and an epi-
leptiform EEG in which the EEG shows only occasionalspikes. The paradigm for treatment in this scenario isthat of transient cognitive impairment [177]. Treatment
for this group is very controversial and requires carefuldocumentation that these spikes are directly linked tothe language, cognitive or behavioral dysfunction. If
treatment is pursued, careful re-assessment at 3 month
intervals with clinical, neuropsychological assessments,and serial EEGs should be carried out.
5. Conclusions
Advances in our understanding of the molecular biol-
ogy of ASD and of epilepsy now allow us to conceptu-
alize intervention strategies that may positively change
the developmental trajectory of both ASD and epilepsy.An emerging approach to target more specifically theASD–epilepsy phenotype is based on our understandingthat abnormalities of synaptic structure and function arecentral to the brain basis of ASD [178] and of epilepsy
[179]. Translation of basic science and mouse model
data will be crucial to the development of clinical inter-
ventions for individuals with both ASD and epilepsy.
Tuberous Sclerosis Complex (TSC), a neurological
disorder commonly associated with both ASD and epi-lepsy provides an informative example on commonmechanisms that can account for both autism and epi-lepsy [180]. In a mouse model of tuberous sclerosis,
treatment with the mTor inhibitor rapamycin has been
reported to prevent epilepsy and reverse learning deficits
[181–183] . Another potential treatment model is fragile
X syndrome in which ASD and epilepsy commonlyco-exist [184]. The emerging understanding of the molec-
ular deficits leading to fragile X syndrome has allowedor the development of interventions that may also havethe potential the potential to treat both epilepsy andASD [185–188] . One other interesting area of focus for
potential treatments of ASD–epilepsy are the genes con-
trolling circadian rhythms that modulate protein com-
plexes important in synaptic development and in thenormal balance between excitation and inhibition inbrain circuits [189]. A mouse model with conditional
deletion of Pten is associated with abnormalities in cir-
cadian rhythms, seizures, and social interaction deficits[190]. This may be a useful model to study the effect of
pharmaceutical interventions on circadian rhythm
abnormalities and assess the effects on social interaction
and seizures. In addition, understanding the role of mel-atonin in regulation of sleep and in cognitive and behav-ioral development [191] and its relationship to ASD and
epilepsy through common clock genes and neurotrans-mitters should provide new targets for pharmaceuticalinterventions [192]. Despite the promise of these exam-
ples the possibility of developing pharmacological inter-
ventions that target both ASD and epilepsy awaits
definitive evidence.
A potentially effective approach to treatment in chil-
dren with ASD and epilepsy is the early identification ofinfants with epilepsy who are at-risk for ASD. Childrenwith epilepsy whose seizures begin in the first 3 years oflife, including those with epileptic encephalopathies, rep-resent one example of those that are at high risk for devel-
oping ASD. This group of infants should be identified
early and treated aggressively with a comprehensiveapproach that includes pharmacological agents or sur-gery and developmentally appropriate psychosocial inter-ventions. How aggressive the treatment should bedepends on seizure frequency, frequency of the epilepti-form activity, and the developmental status and trajectoryof the individual infant. It is our belief that the develop-
mental trajectory of those at-risk infants can be altered
positively secondary to early, intensive, developmentallyappropriate interventions that should be in place priorto development of the full-blown ASD phenotype.
Early identification of infants at-risk for ASD is also
essential to determine if epileptiform activity can alterthe developmental trajectory of these infants. Severalinvestigators are currently engaged in longitudinal stud-
ies of high risk infants with older sibling diagnosed with
an ASD. The “baby sibs ”studies are identifying the pre-
ASD behavioral profile of at-risk infants and toddlersand these studies suggest that by 12 months of age someof the siblings who are later diagnosed with autism maybe distinguishable from unaffected siblings and fromcontrols at low-risk for autism [193–198] . These studies
linked to neurophysiological studies may help determine
the role if any of abnormal electrical activity in the
development of ASD.R. Tuchman et al. / Brain & Development 32 (2010) 719–730 725

Dawson [43]has postulated that a combination of
risk genes and early environmental factors puts certaininfants at-risk for the development of ASD. One couldpostulate that seizures or epileptiform activity may beone of the environmental factors that in at-risk infantsleads to altered social interaction and consequently to
atypical development of the neural networks critical
for social and communicative interaction. Once this pro-cess evolves there is a lack of further developmentallyappropriate social communicative feedback amplifyingthe abnormal developmental trajectory, leading to thefull ASD syndrome. The hope is that pharmacologicaland behavioral interventions can alter these early devel-opmental processes and put an infant back on a more
typical developmental trajectory.
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