te

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drome. Its diagnosis continues to depend on the recogni-

presented by 11 childrenwho were clearly distinguishable

the 1980s of standardized instruments. The firstmajor in-

more complex instruments provided standardized andfine-tuned symptom definition, assessment procedures,

DSM-IV diagnostic requirement for six signs, includingat least two in the social area, one in the communication

Handbook of Clinical Neurology, Vol. 111 (3rd series)Pediatric Neurology Part Ifrom their peers, even from a nonprofessional perspec-tion of a cluster of overt positive and negative clinicaltraits (symptoms), a situation that requires agreementamong experts. Kanners view of autism was relativelyclear-cut; his initial definition summed the particularities

and scoring which corresponds to DSM or ICD diagnos-tic criteria. Cut-off scores for diagnostic areas wereintroduced. A global cut-off corresponded to theSPECTRUMBOUNDARIESANDEPIDEMIOLOGY

More than 65 years after its initial recognition byKanner, autism is still considered a behavioral syn-

strument was a short rating scale (CARS) which shouldnow be regarded at best as a screening instrument. Thiswas followed by lengthier and more complex standard-ized diagnostic instruments (SDIs), in the form of a par-ent interview (ADI) andobservation scale (ADOS).TheseThe autistic spectrumcurrently encompasses three clinicalsubtypes: autism per se, Asperger syndrome, and Perva-sive Developmental Disorder Not Otherwise Specified(PDDNOS), all under the overarching DSM-IV categoryof Pervasive Developmental Disorders. Its most recog-nizable core, autism, is a precocious behavioral constella-tion of social and communication atypicalities associatedwith apparently restricted interests and repetitive behavior(RIRB), together with an uneven ability profile. Autism isassociated with multiple but heterogeneous genetic, func-tional, and structural variations whose established linkswith the autistic behavioral and cognitive phenotype areyet minimal. The heterogeneity of causative mechanismsand associated conditions implicated in autism requiresa broad expertise inneuroscience.This gives pediatric neu-rology a central role in the recognition of autism, the as-sessment of co-occurring conditions, and the treatmentof some of its associated difficulties. This chapter will fo-cus on current understanding and diagnosis of autism aswellasavailablesupport,withanemphasisonneurologicalaspects of autism during childhood.Chap

The autisti

LAURENT MOTTRON1,2*1Department of Psychiatry, University

2Centre dExcellence en Troubles Envahissants du DeveloppeMontral, Q

O. Dulac, M. Lassonde, and H.B. Sarnat, Editors 2013 Elsevier B.V. All rights reservedtive. None of the children described by Kanner had a

*Correspondence to: Professor Laurent Mottron, Hopital Riviere-d

Canada. Tel: 514 323-7260 ext: 2173, E-mail: mottronl@uniserve.cor 29

spectrum

D MICHELLE DAWSON2

Montreal, Montral, Quebec, Canada

nt de lUniversit de Montral, Hopital Rivire-des-Prairies,ec, Canada

recognizable neurological genetic syndrome in additionto autism.All had strong speech atypicalities and/or delay.None of these children was considered by Kanner to beintellectually disabled, but their intelligencemanifested it-self in an atypical way. Autism was stable over time,though some developmental transformations were origi-nally described then later elaborated on in Kannersfollow-up papers. Lastly, autism was thought to be rare:the first attempt at epidemiology based on early attemptsat standard criteria revealed a prevalence of only 4/10000.

The situation ismuchmore complex now, particularlywith respect to other-than-autism autistic spectrum diag-noses (ASDs). ASDs are now considered commonplace,with considerable variability in apparent conformity tosocial norms, and in adaptation, intelligence, and co-occurring conditions. Clinicians and researchers nowhave to cope with the transient and unsatisfactory resultsof demands for categorical diagnosis required by the de-velopment of research, combinedwith the pressure of so-cial recognition and service allocation. How did we get tothis point? One important factor has been the creation inarea, one in the RIRB area, and one additional sign.

es-Prairies, 7070 Perras Boulevard Montreal, Quebec H1E 1A4,

m

NDThe ADOS and ADI quickly became the diagnosticgold standard worldwide, first for research purposes,then in clinical settings, and ultimately in service provi-sion. Autism is now defined by ADI and ADOS, a situ-ation that presents pros and cons. These SDIs stimulatedresearch into prototypical autism by standardizing thediagnoses of participants. The modeling of phenotyperecognition by these diagnostic instruments also hadma-jor consequences on the current broadening of autismcriteria. SDIs helped to make the diagnosis of autismpossible in individuals scoring in the normal range ofmeasured intelligence, but also in individuals alreadyidentified with another condition, a situation which in-creased phenotype heterogeneity. Accordingly, the spec-ificity of SDIs has been demonstrated toward specificgroups of idiopathic intellectual disability or language/learning disorders, but not toward other specific groupsof neurodevelopmental conditions, for which the autismscore may range from marginally to strongly positivebased on these criteria. Such a lack of validation, whichmirrors the absence of exclusion criteria in the DSM-IVdefinition of autism toward syndromes other thanschizophrenia, has considerably blurred the boundariesof autism. This is especially the case for differential di-agnoses between ASDs with typical speech level andneurodevelopmental conditions with limited or no im-pact on measured intelligence, such as Tourette syn-drome or some presentations of ADHD.

SDIs also had a major impact on increasing the me-dian measured intelligence or developmental level ofthe population meeting diagnostic cut-off and then,conversely, in limiting its upper range. Accordingly,meeting ADOS or ADI cut-offs is quasi linearly depen-dent on measured intelligence, with systematic reachingof cut-offs for children whose measured mental age isunder 15 to 18 months. These instruments also miss somevery intelligent individuals (especially after puberty),who nevertheless test positive for autism criteria accord-ing to expert judgment. In addition, diagnostic cut-offson the SDIs have the damaging effect of likening autismto a behaviorally unidimensional category, despite ge-netic independence of some of its overt behavioral traitsand a diagnostic threshold that can be reached by anenormous number of different combinations of pheno-typic dimensions. SDIs are, however, indispensable topinpoint a prototypical category, in which both clinicaland research purposes are grounded. In particular, SDIshave contributed decisively to ascertain the distinctionbetween autism with or without intellectual disability,and intellectual disability without autism, as well as toimpose on clinical settings the notion that individualsscoring in the normal range of measured intelligence

264 L. MOTTRON Acould fully satisfy the diagnostic criteria.Anothermajor contribution to evolving views of autism

was the description by Wiener psychiatrist Hans Aspergerof a related condition in a group of adolescents of typicalintelligence and without speech or developmental delay.The recognition of the partial overlap between Aspergersyndrome and Kanners autism had the effect of addingto the initial autism category a group with nondelayedspeech development, but showing signs in the social andRIRB areas similar to those encountered in autism.

But more important, a standardized definition ofautism (autism defined as the SDIs) contributed to raisethe rate of diagnosis among a large number of childrenwho shared more similarities with autism than with anyother diagnostic class, without fully satisfying the SDI di-agnostic criteria. This resulted in inflatingdramatically thecategory of atypical autism (ICD-10) or PDDNOS (DSM-IV), sometimes simply called other ASD. Conversely,the use of a cut-off for consensual autism had the collat-eral effect of rejecting subthreshold children out of theautism category, and consequently, out of the researchfocus. Therefore, whereas autism is plausibly the empiri-cally best-defined DSM-IV condition, the many timeslarger PDDNOS category is one of the least-defined. Itrequires the presence of some signs in the relevant diag-nostic areas while still being subthreshold for autism orAsperger syndrome. Perhaps unsurprisingly, inter-raterexpert agreement for PDDNOS is less than 50%.

The recognition of an inventory of diagnosable con-ditions associated with the autistic spectrum phenotype(as per the SDIs) has resulted in the addition of another10 to 15% of individuals now described as presentingwith syndromic (or secondary) autism, in contrast withidiopathic or primary autism. There are antagonisticviews of the distinction between primary and secondaryautism. One is that if an additional condition is present ina small percentage only of the autistic spectrum, thenthis condition has in fact produced a phenocopy of pri-mary autism, that is, it mimics a phenotype characteriz-ing a certain condition via a completely differentmechanism. In contrast, autism may represent the finalcommon pathway to an indefinite number of mecha-nisms, thus making secondary autism an opportunityto understand idiopathic autism and creating in effecta human model of autism. In our opinion, the latterposition puts an excessive burden on a transient and un-founded consensus on phenotypes. As a reflection ofthis ambiguity, current classifications of autistic-likeconditions in the presence of another identified neurode-velopmental diagnosis are somewhat arbitrary. Syn-dromes whose phenotypes present a superficialresemblance with autism but are associated with a spe-cific cause (e.g., Rett syndrome) are included in PDDbut not in the autistic spectrum, despite satisfyingDSM-IV criteria for autism. In contrast, a child with

M. DAWSONfragile X who also satisfies these criteria will rather beconsidered autistic on Axis 1 and fragile X on Axis 3.Meanwhile, some autistic-like behavioral trajectories,

fined autism is usually not reliably discernible before the

ICfor example those associated with visual impairment,would instead be considered phenocopies.

As a result of these multiple additions to its originaldescription, autism was eventually surrounded by themuch broader category ofASDs. Variation in prevalenceof autism per se has not been dramatic (reported as2/1000 in numerous studies since the mid-1990s), given de-liberate increases in public awareness, planned increasesin availability of services (including diagnostic services),and a purposeful improvement in case finding. How-ever, with ASDs, aggressive ascertainment of secondaryPDDNOS or atypical autism in children already receiv-ing services for other diagnosable conditions hasresulted in what appears to be very high prevalence (inone study, 11.6/1000), even when Asperger syndromeis quasi nondiagnosed. Within the same study sample,using the same SDIs, the same diagnosing clinicians,etc., differences in diagnostic definition, some of themvery subtle, can be responsible for a fourfold differencein prevalence estimates. Throughout existing epidemio-logical studies, the most variation and imprecision inprevalence is due to the PDDNOS (or atypical autism,or other ASD) category.

Several characteristics of the autistic phenotype rele-vant for epidemiological studies reveal by their variabil-ity the extent to which the current delineation of theautistic spectrum phenotype is malleable. Sex ratioranges from a state of quasi balance between boys andgirls in the case of children with secondary autismwho are considered intellectually disabled, to as manyas 10 boys for one girl in the case of children with Asper-ger syndrome. Asmuch as a sex ratio in favor ofmales isan important component of the autistic phenotype, thissuggests that primary and secondary autism are of adifferent nature, or that there is a problem withphenocopies. The proportion of autistics regarded asintellectually disabled has fluctuated greatly throughthe decades, depending on how autism has been definedand on how intelligence has been measured. In addition,the current reported prevalence of epilepsy ranges from5 to 40% of autistic individuals. Like sex ratio and intel-lectual disability, the prevalence of epilepsy differs con-siderably according to whether autism is secondary oridiopathic. There are currently no studies on the preva-lence of epilepsy in samples with measured intelligencein the normal range and from which secondary autismhas been excluded. Clinical evidence is in the directionof a prevalence of epilepsy in this population that isnot much higher than in the nonautistic population.The often-repeated figure of 2030% is clearly an over-estimate, and would if anything characterize only sec-ondary autism, where epilepsy is considerably more

THE AUTISTfrequent, as well as microcephaly and intellectual dis-ability. This aggregation, along with the above-mentioned gender balance, again points toward amiddle of the second year. In secondary autism,manifes-tations of the first diagnosis and especially motor delaysoften precede or mask autistic signs. A decrease in peer-oriented initiatives and reactions, including joint atten-tion, orientation toward a parents voice, as well as smile,babbling and gestures coupling during interactions withparents andpeers, is generally the first observedmanifes-tation. Visual fixation on objects that is atypically pro-longed or under unusual angles may be present at thattime but is less obvious or salient to observers. A periodof quasi absence of oral verbal expression typically fol-lows until 3 to 5 years of age, when echolalia, then stereo-typed speech, appear. In less than 10%ofautistics, speechseparate status for primary and secondary autism. Also,the reported bimodal occurrence of the age of first sei-zures (in infancy or in adolescence) as a characteristic ofautistic epilepsy has to be modulated by the existence ofsimilar age peaks for the first seizures in the generalpopulation. In sum, uncertainty about the prevalenceof autism and its major neurological and demographiccorrelates is a consequence of current standards ofclinical phenotype delineation (the SDIs), the absenceof exclusion criteria toward other neurodevelopmentalconditions, and the arbitrary nature of any categoricaldelimitation of continuous behavioral phenotypic traits.

DIAGNOSTIC ISSUES

Although autism is a brain-based condition, pediatricneurology is not the main entry point of autistic childreninto the healthcare system. Moreover, the first assess-ment of ASDs requires about 2 days of multidisciplinaryinvestigations, including about 5 hours for the use ofSDIs, which is beyond what is expected of a child neurol-ogist. Autism tends to be first suspected by parents orsometimes by others such as daycare staff. General phy-sicians, pediatricians, child psychiatrists and, increas-ingly often, specialized ASD clinics confirm thediagnosis. Referrals to neurologists are limited to com-plex or unclear clinical situations, including epilepsy aswell as medical and genetic conditions with a neurolog-ical expression and a greater-than-chance associationwith ASDs or a partial clinical overlap with its criteria.The child neurologist may then be the first to detectin a child the cluster of atypical social interaction signs,verbal or nonverbal communication delays or atypical-ities, repetitive behaviors, restricted interests, and/oran uneven competence profile.

The diagnosis can be challenging as each DSM crite-rionmay have a considerably different expression acrossdevelopment, from toddlers to adolescents.Narrowly de-

SPECTRUM 265will not develop, but in the majority of cases, speech willflourish, still varying considerably in terms of functionalvalue. The maximum number of recognizable signs is

tive abilities, does not impact on nonverbal social interac-

NDobserved around the ages of 3 and 6 to 7, due to the pres-ence by this age of language signs which are characteris-tic if not definitive, and the general lessening of apparentsocial atypicalities with age. The notion that autism is alifelong condition has to be tempered by the absence ofpredictors of adaptive outcome at toddler age,which var-ies considerably. SDIs therefore take the 4 to 5 years ofage period as the time frame during which retrospectiveascertainment has to take place, whatever developmentaltransformation occurs. The variability of outcomesseems to be directly dependent on two factors: how earlythe diagnosis was made (the later the diagnosis, the morestable it is), and howclose to prototypical autism the childwas at this age (the greater the distance from the proto-type, the less stable the diagnosis). The developmentaltrend of strictly defined autism contrasts with that ofAsperger syndrome, which may involve precocious andspectacular speech abilities.

The most difficult diagnostic issue consists in differ-entiating the apparent decrease in socio-competence in-herent to any neurodevelopmental diagnosis, as well asthe restriction in the variety of interests resulting fromany developmental delay, from their ASD equivalent.A full psychiatric investigation of differential diagnosisis justified in the presence of the major autistic traits,whether or not a neuropsychiatric co-occurring condi-tion is suspected. The main neurodevelopmental condi-tions of psychiatric relevance whose phenotypeoverlaps with the autistic spectrum include Tourette syn-drome, ADHD and developmental dysphasia in theirstrongest forms, childhood depression, and socialphobia; with current SDIs there may also be an overlap(quasi-autism) with early development arisingfrom extreme deprivation (e.g., Romanian orphans).Early-onset schizophrenia in its prototypical form isnot a diagnostic issue, but schizoid personality is cur-rently one of the differential diagnoses of Aspergersyndrome.

In the presence of incontestable psychiatric diagnosisanterior or alternative to ASD, we suggest applying aneconomy principle, i.e., answering the following question:can the socio-communicative atypicalities or limitation inthe variety of activities be explainedmore economically bythe first diagnosis? For example, an individual presentingwith strongTourette syndromewill display poor social ad-aptation due to attention deficit, irascibility, and side-effects of his temper, with the result of limiting the varietyof his activities according to what he successfully pro-cesses. This will lead him to score positively for PDDNOScriteria, but this second diagnosis will neither provide in-formation relevant to intervention nor contribute to a bet-ter understanding of his adaptive difficulties, which will

266 L. MOTTRON Astill have to be addressed in a Tourette syndrome frame-work. A similar position is recommended in the presenceof major ADHD or early deprivation.tion, this syndrome is inherent in its narrowsense toa largefraction of autistic individuals. One third of autistic indi-viduals may fall under this additional diagnosis, whichnevertheless needs to be distinguished fromdelayed echo-lalia and stereotyped speech intrinsic to the autismdiagno-sis. Therefore, in the presence of other autism diagnosticcriteria in the three major areas, developmental dysphasiashould not exclude the search for ASDs. In addition, pos-itive scoring for ADHD criteria is the rule in a majority ofchildren with Asperger syndrome, and consequently, itshould not be considered an exclusion criterion for this di-agnosis.Epilepsyand regression share a certainnumber ofdiagnoses and mechanisms in the context of ASDs. Mostpersistent forms of childhood epilepsy, especially preco-cious ones and regardless of their cause, produce complexbehavioral regressions overlapping with autism criteria.Regression with epilepsy is more dramatic than the lossof the firstwords, typically numbering less than ten,whichsignals autism for one quarter of autistic children. It alsooccurs at an earlier age (West syndrome) or later age(LandauKlefnersyndrome) than is thecasewithapparentlost speech in autism.

A noticeable syndrome constellation is that of tuber-ous sclerosis, epilepsy, and autism. Tuberous sclerosis isfound in 8 to 14%of individuals displayingnarrowautismwith epilepsy, and is thereby 100 times more frequentamong autistics than in the general population. TS is alsoone of the most important causes of West syndrome,itself associated with dramatic behavioral and cognitiveregression. This results in a clinical picture scoring posi-tive on autism criteria, but also with a development ofautistic signs earlier than in idiopathic autism, and ameasured age equivalent under the threshold for wheredistinctions between autism and intellectual disability be-comes possible, that is, around 18 months. Lastly, partialseizures are difficult to detect clinically in anautistic child,and even if their prevalence may not be higher in autism,they have to be investigated in the presence of dramaticchanges or discontinuity in cognitive performance.

NEUROLOGICAL ETIOLOGYANDINVESTIGATIONS

Models

As a consequence of the phenotypic and causative het-Conversely, some neurologically relevant conditionsare so frequent in ASDs that they should lead to a system-atic examination ofASDwhen they are the entry point forneurological examination.Whereas puredevelopmentaldysphasia, despite definitional limitations in communica-

M. DAWSONerogeneity of ASD, the search for a unique and commonneurocognitive mechanism for all individuals sharingASD criteria is no longer a research purpose.

ICInformative similarity between two autistic phenotypesranges frommaximal (e.g., between two idiopathic autis-tic children sharing the same variant genes and cognitiveprofile) to minimal (e.g., between two individuals withsecondary autism differing in their related neurodeve-lopmental condition). There is also the possibility of littleor no informative similarity between primary autism andsecondary autism phenocopies. We will therefore limitour presentation of current models to idiopathic autism,as each type of secondary autism requires a specificmodel of the relationship between the two diagnoses in-volved. Even if limiting ourselves to primary autism doesnot eliminate the heterogeneity of mechanisms at the ge-netic level, it should help preserve a relative homogeneityat the microstructural, brain functional, and cognitivelevels, at least within ASD subgroups.

ASD is now considered a variant of typical informa-tion processing, i.e., the way humans perceive, memo-rize, manipulate and attribute emotional value toavailable information. This variation consists in the lessautomatic or mandatory, compared to nonautistics,higher-order processing of incoming information (cate-gorization, purposive integration, and attribution ofemotional value). A more optional, but not in any wayabsent, relation among cognitive processes allows fora greater than typical role of perception, including intasks not considered to be perceptual in nonautistics.For typical individuals, a major way to attribute valueto incoming information consists in automatically index-ing it with a social value (personal benefit, socialadequacy, consistency with collective interests). Autisticindividuals are therefore judged from a typical view-point to differ most visibly from their peers in theirsocial interests, overt emotions, and more generallysocially oriented behavior. However, there is nowa consensus that autistic information processing differ-ences are domain general, encompassing informationregarded as nonsocial (e.g., visuospatial processing).While nonautistic cognition is dominated by an early,automatic, and exclusive bias towards social infor-mation, the predominance of perception in autisticcognition allows for enhanced processing of environ-mental regularities in visual and auditory information.

Enhanced perceptual abilities, or peaks of ability, aresolidly demonstrated. They extend from enhanced dis-crimination of low-level psychophysical auditory (pitch)and visual (luminance-defined gratings) information topattern detection (e.g., visual search) and manipulation(mental rotation, visuospatial construction). Positiveemotions may be apparently less related to social infor-mation, although not impaired per se, as positive emo-tions are associated with strong focused interests and

THE AUTISTthe sharing of these. In contrast, and despite immenseefforts, no cognitive deficit has unequivocally beenfound in cases of autism, once the effect of measuredintelligence has been removed. Understanding of humanintentions in autism, an overt index of social cognition,has been shown in multiple studies to be at least at thetypical level. Numerous findings related to complex pur-posive actions, problem-solving, and executive functionsyield apparent advantages and apparent disadvantages,depending on experimental design and task demands,but no overall picture of a deficit. Long-term memoryperformance follows measured intelligence, but it isalso less influenced by semantic or emotional propertiesof the memorized material than is the case withnonautistics.

Test scores in the range of intellectual disability in au-tism come with several distinct explanations dependingon the ASD subgroup under study. The consensual pres-ence of a significant, and probably dominant, fraction ofidiopathic autism with a typical level of measured intel-ligence indicates that intellectual disability is not a man-datory component of ASDs. Another percentage ofapparently intellectually disabled individuals actuallydisplays a normal nonverbal IQ level, indicating that dif-ficulties with speech or language, whatever their cause,play a strong role in how the abilities of some autisticpeople are judged. Yet another fraction of autistic indi-viduals with low measured intelligence probably corre-sponds to the long-term effects of impoverished inputdue to unavailability of material that they would be ableto process well, such as in the case where an autistic withdelayed or sparse speech is assumed to have very limitedabilities or potential. This mechanism can be inferredfrom analogous situations involving deaf adults whowere exposed neither to oral nor to sign language, asautistics seem more dependent than typical individualson access to specific kinds, amounts and arrangementsof information that may not be easily or at all available.Lastly, intellectual disability in autism coincides, inmanycases, with secondary autism, and follows the sameexplanations as those used for intellectual disabilityper se (e.g., reduced dendrite spines).

Second-generation brain-based models now deempha-size the putative action of single cognitive deficits withcascading effects, such as amygdala or cerebellum defi-cits, in favor of distributed reorganization among brainfunctions and levels. Most structural studies find smallercells and atypical minicolumnar organization in gray mat-ter, but no evident neurochemical modifications. To-gether with increased gray and white matter volume,this indicates that small-scale neural networks are modi-fied in autism, although the relationship of these modifi-cations with perceptual peaks and autistic behavior is asyet unknown. At a macroscopic, regional level, imagingstudies (PET, SPECT) point to diminished oxygen con-

SPECTRUM 267sumption in temporal regions. Several functional MRIstudies demonstrate diminished activity in frontal andtemporal regions but enhanced activity in the visual

the use of SDIs in a context other than an autism special-

NDized clinic, as they require a high amount of expertise intheir administration and in ASDs in order to avoidmisinterpretations.

Brain imaging is one of themain focuses of interest inASD research. However, its clinical use is limited, withno justification for structural MRI in the absence ofother symptoms, for example, epilepsy or otherwise in-coherent clinical information. Increased overall brainsize, as well as absolute or relative decrease of the ante-rior and posterior parts of the corpus callosum section, isthe most replicated structural characteristic in autism.Contrary to most other neurological markers, these pe-culiarities do not aggregate with intellectual disabilityand/or additional diagnoses, which in turn make theman intense focus of research. An increase in brain sizeconsistently spares frontal lobes but affects gray andcortex. This latter pattern of activity cannot be straight-forwardly equated with a functional deficit, as manyfMRI studies find that autistic participants perform tasksat least at the same level as their nonautistic comparisongroup, despite strong differences in topography of activ-ity. Therefore, some reallocation of regional brain func-tions must take place. For example, typical or superiorperformance in working memory or problem-solvingtasks is obtained in the presence of an inverted balanceof frontal-occipital activation. Decreased inter- and intra-hemispheric connectivity has been supported by most dif-fusion tensor imaging studies. Such reduced functionalcrosstalk between brain regions is also consistent withthe diminished section of the corpus callosum, a situationwhich is consistently found in ASDs.

Investigations

The role of neurology in autism differs dramaticallywhether it pertains to research,where it ismajor, or to clin-ical settings, where it is less so, given our ignorance of theprimary cause of autism and therefore our inability toaddress it at this scientific level. Whatever uncertaintyremains about the actual relationship between neurologi-cal features like epilepsy, epileptic regression, intellectualdisability, neurogenetic syndromes, andautism, these con-ditions occur concurrently in clinical settings and justifysystematic clinical, and if relevant, paraclinical investiga-tions. When ASD is suspected, its diagnosis in a pediatricneurological context should follow a threefold procedure:unfocused search for neurological, genetic or medicalsigns; clinical characterization of developmental level inthe cognitive, language and motor areas; and explicit as-certainment of DSM-IV criteria and their interpretationin relation to thepreviousvariables.Wedonot recommend

268 L. MOTTRON Awhite matter to a similar extent. Brain size increase is as-sociated with head size increase, and is usually around2 SD above median head size. In rare situations evokingCowden syndrome and a mutation of PTEN genes,macrocephaly is associated with tumors. Autistic macro-cephaly coincides with the first behavioral autistic signsoccurring around the end of the first year. Some but notall studies report its normalization at an adult age, whileothers found macrocephaly in 30% of adult autistic indi-viduals compared to 2% of controls. Other cerebralstructures present inconsistent variations which cannotbe interpreted even in a research context.

Medical etiologies with neurological expression areof very limited application in autism. Allmedical hypoth-eses about large-scale causes of ASDs can be firmly dis-carded. The putative role of vaccines and exposure tolead or mercury as widespread causes of autism is nolonger a scientific issue. This strong statement shouldnot be confounded with the demonstrated neurologicalcomplications of vaccination and metallic exposure inan extremely limited number of cases. In the latter situ-ation, as for any neurodevelopmental condition, a partialoverlap with an autistic phenotype is possible. As for thehypothesis that gastrointestinal symptoms are moreprevalent in ASDs than in the typical population, evenpreliminary data are missing, making this model a prior-ity neither in clinical investigations nor even in research.A safe guideline in this regard is to examine each individ-ual for medical signs, without being influenced by cur-rent thinking, but nonetheless without discarding thepossibility when one child happens to encompass oneof these models of putative medical cause of autism.The most frequent medical condition which mimics anautistic profile is sensorial impairment, specifically con-genital or early blindness and Leber amaurosis. Rarereported medical conditions are mitochondrial syn-drome and prenatal exposure to valproic acid, but rou-tine metabolic testing is not recommended.

Inborn errors ofmetabolism presenting amore or lessphenotypic resemblance with autism (usually combinedwith intellectual disability) are quite numerous, the mostfrequently reported being phenylketonuria whenuntreated, creatine deficiency syndromes, disorders ofpurine metabolism adenylosuccinate lyase deficiency,disorder of GABA metabolism succinic semialdehydedehydrogenase deficiency, disorders of pyrimidinemetabolism dihydropyrimidine dehydrogenase defi-ciency, homocystinuria, histidinemia, biotinidasedeficiency, infantile ceroid lipofuscinosis and other lyso-somal disorders, and Sanfilippo syndrome. Metabolicscreening should be used based on suggestive clinicalfindings like modification of alertness or tonus, earlyand intractable self injury, intellectual disability, dys-morphisms, and any medical, particularly digestive,

M. DAWSONsymptoms. Together, all these conditions account forless than 1% of early autistic phenotypes.

GENETIC ETIOLOGYAND

ICNeuropsychological and communication characteriza-tion of ASDs is required for diagnosis as well as foreducation and support, at all ages and developmentallevels. For a nonverbal child or a child who has not yetreached the age of language development, psychologicaltesting may be impossible due to lack of compliance orcomprehensionof task instructions. Thismaymeanadapt-ing test administration procedures, the modeling ofanswers, or modifying the way information is collected(for example, activities could take place in natural settingsand information gatheringwould be limited to an in-depthinterview with caregivers). While testing situations aregenerally pleasant to autistic children, nonverbal taskswith self-explaining instructions may sometimes be theonlyway tomeasure their competence level. The cognitiveand communication assessment must answer four majorquestions: Is the average level of cognitive performanceat the normal or the intellectually disabled level? Is thecognitive and communication profile consistent with anASD subtype? What is the nature of the communicationchannel actually allowing for exchange of information?Are there any associated cognitive deficits?

The interpretation of intelligence level in ASD is chal-lenging in that some tests and activities clearly underesti-mate cognitive level and display an isolated, low level ofperformance, lower than that associated with the majorityof tasks and representing the childs baseline level. In con-trast, other tasks are performed at a level markedly supe-rior to this baseline, making the decision about which levelof performance adequately represents intelligence an es-pecially difficult one. In autism per se, especially in thefirst years, language-mediated tasks requiring the under-standing of verbal instructions are the most difficult toperform. However, vocabulary tasks requiring the childto point to answers or to decode words may be performedat a typical or even superior level. The lowest performanceis usually obtained in the comprehension subtest of theWechsler scale, which measures the ability to face a newsocial situation presented verbally by means of a verbalanswer. The highest performance, frequently calculatedat 4 to 6 SD above this low performance, is found in theblock design subtest and in nonverbal fluid intelligencetasks (Ravens ProgressiveMatrices). OtherWechsler sub-tests typically range between comprehension and block de-sign tasks. Whereas low scores in an individuals profilemaypredict anoverall adaptation todailydemandswithoutaccommodation, high scores predict abilities and intelli-gence level in adapted conditions. This pattern of perfor-mance diverges markedly from that observed in theAsperger subgroup, where some verbal tasks (except thecomprehension subtest) often present a level of perfor-mance superior towhat isexpectedat thechilds chronolog-

THE AUTISTical age. In contrast, coding and digit span subtests areusually associated with the lowest levels of performanceINVESTIGATIONS

Models

Knowledge about genetic influence onautismhas reacheda paradoxical state of the art, combining strong scientificevidence ofhighheritabilitywith limited actual determina-tion of genes and modes of transmission involved, andclinical applications restricted to a small subgroup of thephenotype. Uncontested epidemiological evidence of fa-milial aggregation of autistic traits provided the first dem-onstration of a genetic role in autism. Differences inconcordance between monozygotic twins (60% andabove) vs. dizygotic twins (around 5%) is considerable,although phenotypic differences between monozygoticautistic twins are often observed. Concordance betweensiblings ranges from 3 to 6%, with a possible 8% for fam-ilies who have more than one autistic child, but there is asubstantial drop in aggregation between first- andsecond-degree relatives. Familial aggregation extends be-yond narrow autism: concordance for ASD increases con-siderably when other ASD subgroups, and a fortiori abroaderautisticphenotype,areconsidered.Familial aggre-gation is greater for probands with highermeasured intel-ligence, which can be explained by the impossibility ofdifferentiating autism from intellectual disability (whosedue to attention difficulties. Asperger children do not dis-play visual-spatial peaks, but interestingly, and in commonwith autistics, score higher on intelligence when it is mea-sured by Ravens Matrices as opposed to Wechsler scales.They also present an enigmatic motor clumsiness, notfound in autism, which is revealed by major difficultiesin writing, cycling, and catching balls. This clumsiness dif-fers fromthemotorapraxia commonlyobserved inautism.

Neuropsychological and communication assessmentshould not solely consist of a catalog of deficits. Itshould search for and reveal successful channels of com-munication and specific areas of ability and transmit thisinformation to caregivers. In the range of intellectualdisability, when using Wechsler scales, one can fre-quently observe among preschoolers a typical level ofunderstanding of nonverbal or pictorial information,and among school-age children, of printed, written in-formation. Extensive cognitive and language testingshould be conducted in order to search for unexpectedand unapparent peaks or deficits. Secondary autismand PDDNOS in particular display heterogeneous cogni-tive profiles, which can be the reverse of the classic au-tistic profile, with dramatic consequences on academicperformance if they are ignored.

SPECTRUM 269heritability is overall lower than that of autism) in verylow mental-age equivalents. A somewhat different and

emphasize at least two different genetic mechanisms.

behavior can be considered a typical autistic expression

NDInstead of common genes with a small, predisposingeffect acting in association, the genetic heterogeneityof autism would mainly result from a large number ofsporadic neo-mutations, including the recently discov-ered copy number variations in 10% of simplex families.Many genes thus involved in ASD are implicated insynaptic transmission, and in neural networks program-ing and development. Those mutations rare genes witha causative effect would occur in critical but multiplepossible regions, different for each child, specificallyin chromosomes 2, 7, 15, and X. They would explainthe emerging relationship between an increased possibil-ity of having an autistic child and an older parental age.Some of these mutations would be transmitted tofemales, more resistant to their penetrance for unknownreasons, and transmitted in a quasi-dominant, mendelianway to the more sensitive male offspring. The lattersituation would correspond to multiplex families. A spe-cial case has to be made for chromosomal rearrange-ment, found in 3 to 5% of ASD individuals, for whicha causative link with the phenotype may or may not bepossible, and which raises various and contrasted conse-quences for genetic counseling.

Investigations

Referral to a clinical geneticist is recommended in thecase of minor dysmorphism or any sign of a recogniz-able neurodevelopmental syndrome. The same is truein the case of multiplex families or families exhibitingsporadic occurrence of a neurological condition associ-ated with autism (e.g., TS, fragile X), or when there is aneed to refine genetic counseling. The list of genetic con-ditions whose phenotypes may present some overlapwith ASD is open, but the most frequently cited, witha reported prevalence rate of less than 5% in autism co-horts, are tuberous sclerosis and fragile X. Other com-monly mentioned conditions, with a prevalence rate ofweaker aggregation is observed between one autistic pro-band and multiple psychiatric conditions in relatives,including mood and anxiety disorders, but the clinicalusefulness of this notion is limited by its imprecision.

The heterogeneity of the autistic phenotype corre-sponds to the very large and heterogeneous number ofgenes implicated in autism studies, most of them beingeither nonreplicatedorproducingonly a small effect size.This has first led geneticists to postulate that an interac-tion of multiple genes, acting with the same strength,would produce by some kind of threshold effect theemergence of a discernible phenotype. However, currentsyntheses account differently for this heterogeneity and

270 L. MOTTRON Aless than 1%, include the following syndromes: Down,Rett, Angelman, PraderWilli, velo-cardio-facial,of extreme confusion and negative emotions. Sincemostself-injurious behavior is sporadic andwithout damagingphysical consequences, it should be addressed as a crisissituation and dealt with as such. Contrastingly, life-threatening self-injurious behavior is part of the pheno-Turner, Cornelia de Lange, LeschNyhan, SmithLemliOpitz, Sanphilippo, Williams, Cohen, Ito,Joubert, FG, ARX, XYY, Klinefelter, PKU, 15q, neuro-fibromatosis, Mobius, and Smith Magenis.

TREATMENTANDSUPPORT ISSUES

There is no medical treatment for autism, in the sensethat an inborn and distributed difference in neuronal or-ganization and functional allocation of brain resources isas yet out of reach of pharmaceutical agents (whichhave, however, been proposed via animal models of,e.g., fragile X). Parental guidance and adaptivemeasures at home and at school, combined withcognitive-behavioral approaches as required for associ-ated conditions, remain the logical way to address mostchallenges. SomeWestern countries have invested a con-siderable amount of resources in early behavioral inter-vention, such as early intensive ABA (applied behavioranalysis)-based intervention involving one-on-one train-ing for at least 20, and up to 40 or more, hours per week.Despite their long history and forceful claims by theirsupporters, these costly and arduous methods are notsupported by good quality research (e.g., randomizedcontrolled trials conforming to standards well recog-nized in intervention and treatment research for the non-autistic population). Ethical issues also remainunaddressed. Therefore the actual effects of ABA-based autism interventions, their benefits and harms,have not been sufficiently established in the short term,and even less so in the long term.

The neurologist should not attempt to normalize di-mensions of behaviors that are intrinsically linked to au-tism, such as trying to impose typical social or otherbehaviors (equivalent to demanding that blind peoplemake eye contact and read in a typical manner); norshould positive focused interests be treated as patholog-ical obsessions. In addition, nobody should try to sup-press in an autistic child what is tolerated in a typicalchild. Sporadic tantrums belong to the typical repertoireof preschoolers, and a less-than-ideal level of activity be-longs to typical children in the 6 to 9 age group. Repet-itive movements should not be targeted in order tosuppress their stigmatizing effect on parents, inasmuchas they do not represent a burden to the autistic childhimself. In most cases of primary autism, self-injurious

M. DAWSONtype of a number of genetic conditions associated withsecondary autism (e.g., SmithLemliOpitz syndrome).

However, some co-occurring features of the autisticspectrum may be successfully targeted. Indication ofphysical or psychological suffering should not automat-ically be interpreted as an autistic symptom and, there-fore, left unexplored. Specific language impairmentsmay be addressed with speech therapy, one-to-one inter-action, or alternative communication channels (e.g., key-boards), but the majority of efforts should concentrateon managing communication with the child in familyand classroom situations. Support for sensory-motordifficulties, including desensitization but also trainingof underdeveloped motor sectors, is usually providedby an occupational therapist. Rare co-occurringobsessive-compulsive disorder or Tourette syndrome,once distinguished from the repertoire of repetitive au-tistic movements, can be medicated if necessary, as isgenerally the case with any co-occurring condition. Thisalso applies to attention deficit, damaging levels of ac-tivity (especially verbal), anxiety disorder, and depres-sive mood in Asperger syndrome. Heavy behavioral

the crisis in that way. For example, most apparent tempertantrums in autistic children of preschool age can be al-leviated by teaching parents how to decode the commu-nicative attempts of their child, how to provide him withinformation and materials that he can process well, andhow to address him in a way that he can understand. Sim-ilarly, depressive mood states in school-age autistic chil-dren are often related to bullying, in which case it is thebehavior of bullies which needs to be addressed.

FURTHER READING

Manzi B, Loizzo AL, Giana G et al. (2008). Autism and met-

abolic diseases. J Child Neurol 23: 307314.Minshew NJ, Sweeney JA, Bauman ML et al. (2005).

Neurological aspects of autism. In: FR Volkmar, R Paul,

A Klin et al. (Eds.), Handbook of Autism and Pervasive

Developmental Disorders. Wiley, Hoboken, pp. 473514.

Moss J, Howlin P (2009). Autism spectrum disorders in ge-

netic syndromes: implications for diagnosis, intervention

THE AUTISTIC SPECTRUM 271problems, such as aggressive behavior or tantrums, in-tractable wandering or the socially damaging pursuitof restricted interests, are possible but rare. They justifya combined cognitive-behavioral and pharmacologicalapproach. Existing studies have shown that the benefitof atypical antipsychotics in this case is very limited,and may even be less than that associated with a placeboeffect. The use ofmedication with autistics should there-fore always follow an in-depth, but unsuccessful inves-tigation of the role of contextual cues in producing acrisis situation, as well as rational attempts to addressand understanding the wider autism spectrum disorder pop-

ulation. J Intellect Disabil Res 53: 852873.Mottron L, Dawson M, Soulie`res I et al. (2006). Enhanced

perceptual functioning in autism: an update, and eight

principles of autistic perception. J Autism Dev Disord

36: 2743.Samson F, Mottron L, Soulie`res I et al. (2011). Enhanced vi-

sual functioning in autism: an ALE meta-analysis. Hum

Brain Map http://dx.doi.org/10.1002/hbm.21307 [Epubahead of print].

Zhao X, Leotta A, Kustanovich V et al. (2007). A unified ge-

netic theory for sporadic and inherited autism. PNAS 104:1283112836.

The autistic spectrumSpectrum boundaries and epidemiologyDiagnostic issuesNeurological etiology and investigationsModelsInvestigations

Genetic etiology and investigationsModelsInvestigations

Treatment and support issuesFurther Reading