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Eur J Pediatr (2008) 167:1091 1101 DOI 10.1007/s00431-008-0764-4

REVIEW

REVIEW

Whats new in autism?

Jean G. Steyaert & Wouter De La Marche

Received: 10 March 2008 /Accepted: 14 May 2008 / Published online: 3 July 2008 # Springer-Verlag 2008

Abstract This review on autism spectrum disorder (ASD) focusses on recent insights in the clinical picture, such as continuity of the phenotype and the concept of broader phenotype, on epidemiology and on clinical issues relevant to physicians, including new methods for early screening and diagnosis, psychiatric and somatic co-morbidity, and the expansion of so-called complementary and alternative treat- ments. ASD is a disorder with mainly genetic causes and recent insights show that a variety of genetic mechanisms may be involved, i.e. single gene disorders, copy number variations and polygenic mechanisms. Technological advan- ces in genetics have lead to a number of promising findings, which, together with other lines of fundamental research, suggest that ASD may be a disorder of connectivity in the brain, at least in a subgroup of patients. It is possible that part of the genetic load in autism actually reflects gene environment interaction, but there is no evidence for purely environmental causes in a substantial number of cases. Clinical research suggests that ASD may be a multi-system disorder in at least a subgroup of subjects, affecting the gastro-intestinal (GI) tract, the immune system and perhaps other systems. Behavioural treatments remain the corner- stone of management, and are mainly aimed at stimulation of the domains of impaired development and reducing second- ary behaviours. These treatments are constantly being

J. G. Steyaert (*) : W. De La Marche Department of Child and Adolescent Psychiatry, Katholieke Universiteit Leuven (UZ Leuven), Herestraat 49, 3000 Leuven, Belgium e-mail: Jean.steyaert@med.kuleuven.be

J. G. Steyaert Department of Clinical Genetics, University Hospital of Maastricht, Maastricht, The Netherlands

refined, but the main progress in this area may be the increase of research on effectiveness.

Keywords Autism . Review . Autism spectrum disorders . Pervasive developmental disorders

Abbreviations

ADHD

ASD

BAP

CAM

Attention deficit and hyperactivity disorder

Autism spectrum disorder Broader autism phenotype Complementary and alternative medical treatments Childhood disintegrative disorder Diagnostic and statistical manual of mental disorders, 4th edition Gastro-oesophageal reflux disorder Landau-Kleffner syndrome Magnetoencephalography Mirror neuron system Picture exchange communication system Pervasive developmental disorder

CDD

DSM-IV

GERD

LKS

MEG

MNS

PECS

PDD

PDD-NOS Pervasive developmental disorder not

NLD

otherwise specified Non-verbal learning disability

SLI

Specific language impairment

TEACCH

Treatment and Education of Autistic and

TSC

related Communication-handicapped Children Tuberous sclerosis complex

Introduction

Since the first descriptions of early infantile autism [ 74 ] and Asperger s syndrome [7 ], scientific findings have taken

first descriptions of early infantile autism [ 74 ] and Asperger ’ s syndrome [ 7

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autism and autism spectrum disorders (ASD) from a rare and intriguing psychiatric condition to a rather common neuro-developmental disorder. Many aspects of the condi- tion remain unclear, while the public expects clinicians in childcare to be well acquainted with it. Both the prevalence of ASD and scientific findings on the subject seem to have exploded in the past two decades. Brain imaging, neuro- science and genetics have generated huge amounts of data, while hypotheses on the pathogenesis, connecting different research levels, are still embryonic. Meanwhile, clinicians must deal with high expectations from parents and patients. In this review, the authors summarise and discuss recent findings on different domains of research in autism, with a particular focus on clinical issues. Emerging theories on the pathogenesis of autism are discussed briefly. The large number of research articles on autism (4,467 PubMed hits for the last 5 years) does not allow a fully unbiassed review of the literature. For the sake of comprehensiveness, a number of older articles were added.

The clinical picture

In 1943, Kanner [ 74 ] was the first to describe the child psychiatric disorder that is, nowadays, still accepted as the typical phenotype of autistic disorder; mostly aloof chil- dren, with limited, bizarre or absent communication, and absorbed by stereotypical movements and interests. The classification systems DSM-IV [ 2 ] and ICD-10 [ 132 ] describe the autism phenotype in three domains: impair- ments in social interactions, impairments in communica- tion, and restricted and repetitive patterns of behaviour and interests. No quantitative statements are made, except that the signs and symptoms should be impairing. The recog- nition of conditions with social-communicative impairment related to autism, but not fulfilling all of the diagnostic criteria of autism, led to the development of the term pervasive developmental disorders (PDDs) [ 124 ]. Be- sides autistic disorder, PDDs include Asperger s syndrome, Rett syndrome, childhood disintegrative disorder and PDD not otherwise specified (PDD-NOS). PDD-NOS satisfies a diagnostic need for children with severe and pervasive impairment in the development of at least one of the symptom domains of autism, but where the criteria for specific PDDs are not met. This has led to diagnostic ambiguity and the term autistic spectrum disorders (ASDs) was introduced in the early 1990s. It is now the preferred term in many European countries. There is still some ambiguity with this term [ 121 ], as some authors limit the term ASD strictly to subjects with mild to severe deficits in the three core domains of autism, thus, including autistic disorder, Asperger s syndrome and less specific clinical pictures. Other authors include the other PDDs,

clinical pictures. Other authors include the other PDDs, consequently equating the term ASD with the term

consequently equating the term ASD with the term PDD. We choose the former delineation, as this defines a more homogeneous group of disorders, with probably more related aetiologies, requiring more analogous therapeutic approaches. One problem of the term PDD-NOS is that it may also apply to a number of subjects with quite different neuro-developmental disorders, e.g. children with severe specific language impairment (SLI) may have pervasive communication deficits and fulfil the criteria for PDD- NOS. The same is true for children with so-called non- verbal learning disorder (NLD) [ 92 , 108 , 109 ], where the phenotypical links with ASD are imprecise, and aetiolog- ical links are even more questionable. The diagnostic overlap between PDD-NOS and other neuro-developmental disorders also requires that clinicians seeing children with ASD/PDD have sufficient k nowledge of other neuro- developmental disorders in order to guarantee adequate differential diagnosis. Finally, even opting for the more restrictive definition of ASD does not solve all problems, in particular, not that of the so-called broader autism pheno- type (BAP). This refers to relatives of subjects with ASD who have some characteristics of ASD but do not fulfil the criteria for it and have little or no impairment [ 40 , 41 , 104 ]. BAP may be present in almost one in three first-degree relatives of subjects with an ASD [ 41 ]. While there is evidence that these symptoms are genetically related to the symptoms in the proband, the concept of BAP is confusing at the phenotypical level: do these relatives have a PDD- NOS, a very mild ASD or just a normal variance? Researchers on the phenotype and genetics of ASD have pushed forward the concept of narrow, ” “ broader and mild phenotypes, spanning the range from definitely impaired subjects to subjects with characteristics of ASD in the range of the normal population [ 128 ]. The question of delineation may be strongly influenced by the research field of the authors, e.g. geneticists will be interested in relatives with mild phenotypes, while communication therapists will rather carry out research on children with severe pheno- types. In conclusion, there is no entire consensus about the terminology and one should check which definition of autism, ASD or PDD has been used by the authors of a research article in order to be sure to which clinical group the findings apply. In this manuscript, we will further use the more narrow definition of ASD, unless there is a specific purpose for mentioning PDD, e.g. in prevalence studies. Another important aspect of the phenotype is the delineation of syndromic versus isolated ASD: in syndromic ASD, the ASD phenotype is a part of a broader genetic condition [53], i.e. tuberous sclerosis complex (TSC, OMIM #191100), Rett syndrome (OMIM #312750), fragile-X syndrome (OMIM #300624), Smith-Lemni-Opitz syndrome (OMIM #270400) and 22q11-deletion (OMIM #192430) [4,

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125]. Together with unique chromosomal anomalies, this group, with demonstrable genetic aetiology, represents approximately 615% of all persons with autism, and the fraction is likely to be higher when micro-array comparative genome hybridisation is used [114].

Epidemiology

Early studies on the prevalence of autism reported prevalence rates in the range of 4 5 per 10,000 children (for an overview, see [ 133 ]). A broader interpretation of the diagnostic criteria and the emergence of the concept of PDDs have led to an increase of the prevalence rates to around 34 per 10,000 children for autism [ 133 ] and 60 per 10,000 for all PDDs [ 30 ]. Baird et al. even found a prevalence of 1% for all PDDs in an urban area [12 ]. Most studies report a male to female ratio of around 4:1 [ 8 , 52 ], possibly higher in persons with normal intelligence. There might be some diagnostic bias however, as the same cut-off scores are used for both males and females, while there are mild gender differences for numerous aspects of typical development. An important question is whether there is an autism epidemic [ 130 ]. As the application of diagnostic criteria has changed, both in persons with normal intelli- gence and with mental retardation, it is difficult to compare different birth cohorts [ 97 ]. Two carefully conducted studies in the US [ 8 ] and the UK [ 30 ] do not report significantly increased rates between different birth cohorts.

A large Canadian study reported a mild but significant

increase in prevalence in consecutive birth cohorts [ 52 ].

The alarming increase in prevalence reported by the media

is largely unsubstantiated. The increase in prevalence of

ASD is mainly administrative and linked to the broadening

of diagnostic criteria and the improvement of diagnostic

capacity [ 100 , 116 ]. Nonetheless, the administrative prev- alence of ASD is still below the prevalence measured in epidemiological studies [116 ]. A multi-site surveillance conducted by the US Centers for Disease Control and Prevention found marked regional differences in the prevalence of ASD [8], ranging from 3.3 per 1,000 to 10.6 per 1,000. Though differences in diagnostic procedures may partly underlie this finding, it may point to environmental effects. A small secular increase in prevalence could also reflect such effects. The high heritability of ASD (see next section) does not rule out neither environmental effects nor geneenvironment interaction.

The biology of ASDs

Kanner, Asperger and several researchers in the 1960s and 1970s suggested underlying biological anomalies. Since the

late 1970s, the focus was directed on the genetic causes [ 50 ] and, very recently, research on other possible causes has begun to emerge.

The genetics of ASDs

Family and twin studies with narrow as well as broad definitions of the phenotype have generated overwhelming evidence that ASDs have a high heritability [ 9 , 49 , 50 , 53 , 83 ]. The concordance rate for autism is 70% in monozy- gotic twins and rises to 90% if broader criteria are taken into account [ 83 ]. It should be noted that the high heritability of ASD may partly reflect gene environment interaction effects, which, in twin studies, cannot be differentiated from pure genetic effects. The average recurrence risk in siblings is around 2 8% in families with one affected sibling [ 95 ]. In families with more than one affected child, it is probably higher. There is evidence for a BAP [ 41 , 103 ]: (first-degree) relatives who have a significantly higher score in a least one symptom domain of ASD but who are not markedly impaired. The BAP is distinct from normal variation [ 33 ]. Several studies dem- onstrated that different domains of ASD are inherited independently [ 56 , 107 ]. These and other findings suggest

a complex heritability of autism, and it is possible that

different genes [ 53 ] and biological pathways contribute to different parts of the ASD phenotype. Besides genetic heterogeneity, there is also important phenotypical hetero- geneity, as demonstrated by the fact that, even in single gene disorders associated with ASD, only a fraction of the subjects with the genetic condition has ASD, i.e. approx- imately 1 in 2 in TSC and 1 in 4 in fragile-X syndrome. More than 20 linkage studies have led to a host of candidate chromosome regions [ 60 ], with limited concordance be- tween the studies. Association studies with candidate genes have led to some positive results [ 53 , 60 ], suggesting a role for the serotonin system, the glutamate system and others [ 102 ]. A limitation of candidate gene association studies is that they require pre-existing hypotheses about the involved neurobiological systems, and these are very limited in ASD [ 119 ]. Other research methods include studying subjects with ASD associated with a single gene disorder or with a unique chromosomal defect affecting only one gene [1 , 26 29 ]. In these genetically relatively simple models, molec- ular biology has already thrown some light on pathways involved in autism [ 102 ]. Many of the candidate genes found so far play a role in synapse formation and plasticity,

i.e. the neurexin [ 77 ] and neuroligin genes [ 68 ], the fragile-

X gene [61 ], the contactin-associated protein-like 2 gene [ 1 ]

and genes involved in the regulated secretion pathway, which plays a role in the secretion of neurotrophic factors [ 26 , 28 ]. These findings support the hypothesis that errors in neuronal connectivity may be causal in at least a sub-

26 , 28 ]. These findings support the hypothesis that errors in neuronal connectivity may be

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population of subjects with ASD [ 57 ]. Recently, a signif- icantly higher frequency of de novo copy number variations (CNVs) was found children with ASD [ 114 ]. However, most of these CNVs are in different loci and, rather, suggest an increased incidence of germ line mutations in the parents of children who develop ASD than that they are loci that might play a role in a larger group of subjects with ASD [ 134 ]. A few chromosomal anomalies (microdeletions, microduplications) have been found to be associated with ASD in a significant number of subjects and are repeated in different study populations, i.e. 16p11.2 [ 81 , 128 ] and 15q11 13[ 53 ]. These various findings suggest that both major gene effects and polygenic mechanisms additive effect of several genes with minor impactcan lead to ASD. It is generally assumed that the former group represents rare variants and the latter group more common variants, though the rare variants group with major gene effects may be more frequent than expected. These different mechanisms predict highly different heritability risks and, consequently, disentangling them is important in the genetic counselling of families with an affected member. As the genetic and biological heterogeneity of ASD becomes more obvious, much attention has been paid to so- called endophenotypes [ 58 , 120 ] as a means to unravel the neurobiology of ASD and facilitate the search for candidate genes. The endophenotype approach proposes that, in psychiatric conditions with genetic heterogeneity, the subjects can be subgrouped on the basis of neurocognitive or biological characteristics that lay between the phenotype and the genotype. There are some early results of this approach, i.e. association of large head circumference and an allele of the HOXA1-gene [ 32 ].

Anatomy and brain imaging

The best replicated anatomic finding in ASD is the acceleration of head circumference growth in infancy [ 38 , 82 ], followed by an earlier deceleration in head circumfer- ence growth [ 36 ]. In infants, the head circumference highly correlates with the total brain volume. Early brain over- growth occurs in children with ASD of all levels of cognitive functioning, but does not apply to all children with ASD. Courchesne and Pierce [ 37 ] found that early brain overgrowth is most pronounced in the frontal lobes. The deregulation of cell growth, apoptosis and/or white matter development in the first year(s) of life have been suggested as an underlying mechanism. Earlier structural and functional magnetic resonance imaging (fMRI) studies suggested anomalies in specific brain structures, e.g. the amygdala, the gyrus fusiformis, the cerebellum and the frontal lobes [13 ]. Many findings have not been replicated [ 45 , 101 ]. A limitation of MRI and fMRI is that subjects are often adolescents or adults and

fMRI is that subjects are often adolescents or adults and that the findings only reflect the

that the findings only reflect the present state of the brain structure or functioning in the subject, and not the preceding developmental trajectory. According to the theory of interactive specialisation of the brain [ 70 , 72 ], abnormalities found in the adult brain may as well reflect a true anomaly in a given structure as the end-stage of compensatory development. In order to understand early brain development in autism, techniques that are applicable in very young children, like magnetoencephalography (MEG) and EEG/ERP may be more promising. The discovery of the mirror neuron system (MNS) [ 43 ], a neural system in primates activated both when the subject performs an action and when it observes the same action performed by another individual, has brought insight in the neural basis of imitation and perhaps of empathy. Imitation has a key role in social cognition [ 55 ]. It is tempting to link dysfunctions in the MNS to early development in ASD. Some brain imaging studies support this proposal [ 39 ], though there is neither direct evidence of MNS damage in ASD nor of the causal direction of the association between MNS dysfunction and ASD.

Autism, epilepsy and developmental regression

Epilepsy occurs in 8 to 42% of subjects with ASD [24 ] and often begins at a later age than epilepsy without ASD. Epileptic abnormalities with out clinical symptoms of epilepsy are frequent in ASD, in particular during sleep [ 11 ]. Even during the day-time, the correlation between clinical paroxysmal phenomena and epileptic EEG abnor- malities is limited in children with ASD [ 76 ]. The association between developmental regression, epilepsy and ASD is even more complex [108 ]. Autistic regression before the age of 3 years occurs in approximately 1 in 3 children with ASD [ 108 ]. In a small number of cases, autistic regression is associated with an epileptic syndrome, i.e. West or Lennox-Gastaut syndrome [18 ]. Language regression with epileptic phenomena may be associated with Landau-Kleffner syndrome (LKS) or with autistic regression. There is evidence that these are two distinct conditions rather than one spectrum [ 94 ]: in isolated language regression, EEG patterns characteristic of LKS are found more frequently than in language regression with other characteristics of autistic regression, and even when EEG abnormalities occur in the latter group, they are generally not characteristic for LKS. Taken together, in a majority of cases with autistic developmental regression before the age of 3 years, no epilepsy or other neurological disorders can be found [ 106 ]. In the case of regression to autism after the age of 4 years, the specific diagnostic category of childhood disintegrative disorder (CDD) is used [ 2 ]. The prevalence of CDD is estimated at less than 1 in 10,000 [ 51 ]. Though still equivocal, there are more argu-

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ments that CDD may be associated with epileptic phenom- ena [ 11 , 23 , 122 ]. In conclusion, in the absence of neurological signs, there is no argument for EEG or brain imaging in the group with autistic regression before the age of 3 years, while EEG is recommended in regression after that age.

MMR vaccination, immunology and gastro-intestinal problems

In 1998, Wakefield et al. published an article that associated measles or combined MMR vaccination, gastro-intestinal (GI) symptoms and ASD [126 ]. Though several co-authors retracted the article and large-scale epidemiological studies have never supported this association [44 , 52 ], the question is still regularly raised by parents and should be answered appropriately. Recently, more attention has been paid to the equivocal association between ASD and GI symptoms. Valicenti-McDermott et al. found a significantly high lifetime prevalence (70%) of GI symptoms in children with ASD compared to children with normal development or with other developmental disorders [ 123 ]. They included food selectivity as a GI symptom, while it is unclear whether this is a consequence of autistic symptoms or a primary GI problem. Levy et al. [ 85 ] confirmed the increased incidence of GI symptoms but found no associ- ation with dietary intake. The reported GI symptoms are various: loose stools, chronic constipation, atypical tummy aches and complaints suggesting gastro-oesophageal reflux disease (GERD). Buie [ 22 ] found GERD in 24% of children with ASD and GI complaints. Jyonouchi et al. [ 73 ] found deregulation in the production of cytokines against some food components, suggesting a role of non- allergic food hypersensitivity. Several studies have de- scribed autoimmune abnormalities and immune dysfunction (for a review, see [ 6 ]), but the findings are inconsistent and there is certainly not enough evidence [ 47 ] to start treatments targetting the immune system, as suggested by some researchers [ 59 ].

Diagnosis and aetiological investigations

Diagnosis of ASD

Amongst clinicians, there is a wide consensus that treatment of ASD should start as early as possible, though hard evidence is rather limited [ 65 ]. The rationale is two- fold. Firstly, that early treatment may curb some autistic characteristics that may have their own developmental momentum started but not amplified by genetic predispo- sition. Early treatment might restore that developmental

trajectory towards more functional behaviour, e.g. if a lack of special interest in human faces in early infancy impairs the development of early social skills and, at the same time, stimulates the development of stereotypical interest for objects than early intervention focussed at stimulating the interest in human faces might improve later social skills. A second rationale is that part of the impairment in ASD stems from secondary behaviour problems, such as fears and acting-out behaviour. Early psycho-education of the environment and behavioural treatment of specific prob- lems may prevent secondary signs and symptoms and improve adaptive behaviour. While early diagnosis is quite straightforward in severe autism, it has become increasingly clearer that ASD has varying trajectories in early develop- ment and that symptoms may overlap with normal developmental variance and with mental retardation [ 111 , 135 ]. To date, there is no diagnostic laboratory test. The diagnosis is clinical and is based on the diagnostic criteria developed in the DSM-IV [ 2 ] and ICD-10 [ 132 ] and is supported by standardised diagnostic instruments, such as interviews and questionnaires (for an overview, see Lord and Corsello [ 86 ]). The Autism Diagnostic Observation Schedule (ADOS) [89 , 87 ] and the Autism Diagnostic Interview Revised (ADI-R) [ 88 ] have been well validated and their combination is now considered as the gold standard for ASD diagnosis [ 16 ]. Nonetheless, they have some limitations, including lower validity in children under 2 years of age [31 ] or when they are used by untrained clinicians. The Developmental, Dimensional and Diagnos- tic interview (3di) [ 118 ] is a new structured interview for the diagnosis of ASDs which offers the possibility to extend the interview to co-morbid disorders. Autism questionnaires require less clinical training than interviews and their diagnostic validity is lower. The current policy in infants and toddlers is a two-stage approach, with wide screening by clinicians with no particular expertise in autism, followed by referral to specialised teams in cases of positive screening [ 34 ]. The validity of autism screening instruments in children between one and two years of age, like the Modified Checklist for Autism in Toddlers (M- CHAT) [ 10 , 14 ], has improved. The American Association of Pediatrics [ 71 ] provides guidelines and screening instru- ments for paediatricians (http://www.aap.org/healthtopics/ autism.cfm ). A comprehensive assessment of the strengths and weaknesses of the child is necessary in addition to the categorial diagnosis of ASD, and should at least include the testing of cognitive abilities, language, motor devel- opment and adaptive behaviour. The latter is of particular importance, as the adaptive behaviour of children with ASD is often significantly lower than their cognitive abilities [ 78 ], leading to overestimation of the abilities of the child.

significantly lower than their cognitive abilities [ 78 ], leading to overestimation of the abilities of

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Comorbid psychiatric disorders

The DSM-IV considers autism as a pre-emptive diagnosis and rules out the concurrent diagnosis of many co-morbid conditions, i.e. attention deficit and hyperactivity disorder (ADHD). Nevertheless, the full criteria for ADHD (approx- imately 25%), Tourette s syndrome (approximately 10%) and other conditions are often present [ 15 , 54 , 66 , 75 ] and may lead to considerable additional behavioural impairment [ 63 ]. It is now increasingly accepted to make these co- morbid diagnoses. A broader knowledge of child psychiat- ric conditions is necessary for a good appreciation of co-morbidity. Structured interviews like the 3di [ 118 ] or the DISC-IV [ 115 ] are additional tools to assess co-morbid psychiatric disorders.

Paediatric assessment

A comprehensive paediatric history and clinical examina-

tion are essential in children with ASD, as these will guide

additional laboratory tests. Recent research [17 , 80 ] on diagnostic yield and practice guidelines like those of the American Academy of Pediatrics [ 71 ] propose a rather conservative approach to additional laboratory tests: audi- ology evaluation in preschoolers, high-resolution karyotype and DNA testing for fragile-X syndrome. There is some debate on whether genetic testing should be performed in all children with ASD or only in children with mental retardation or dysmorphic signs. Metabolic and other targetted tests or brain imaging can be performed on clinical indication. EEG is warranted when neurological signs or paroxysmal phenomena are present and in the case

of regression after the age of 3 years. If performed, long

registration is recommended, and, if possible, including

sleep deprivation EEG [ 76 ].

Treatment issues

Behavioural treatments

Nowadays, social and functional communication abilities are considered to be a priority in early treatment [ 105 ]. Earlier behavioural programmes focussed on the acquisition

of speech in children with autism. There is now a growing

interest for developmental-pragmatic approaches in which the focus is not necessarily spoken language [ 105 ], but functional communication, like teaching the child to express what he or she wants and feels by diverse means. The Picture Exchange Communication System (PECS) [ 20 , 21 , 25 ] has been developed as an effective method to teach communication to children with autism. In the past decade, different approaches have been studied for their effective-

different approaches have been studied for their effective- ness and long-term outcome, but clear differences between

ness and long-term outcome, but clear differences between the programmes have not yet emerged [ 105 ]. The most important factor of success is an individualised approach [ 96 , 98 ]. In children with ASD and normal acquisition of spoken language, the need for training social communica- tion skills remains present. Individual or group training programmes have not shown much effectiveness, as pupils with ASD often do not generalise the acquired skills to other contexts, and more success is expected from fostering social communicative competence on-site across the differ- ent situations of an individual s day [91 ]. To target skills other than communication, or to change dysfunctional symptoms, strictly structured behavioural interventions are being supplemented with naturalistic behavioural interven- tions [ 67 , 113 ]

Pharmacotherapy

To date, it has not been proven that psychopharmacother- apy may lead to significant improvement of the core symptoms of ASD [ 48 ], while it may reduce secondary or co-morbid symptoms to some extent. Miracle therapies like secretin treatment have soon proved to be unfounded [ 84 ], and the best consequence of the secretin hype was that it demonstrated that the research community has an ability to respond faster than in the past to such claims [ 110 ]. Due to the heterogeneity of clinical presentation and most impair- ing symptoms in ASD, it is difficult to set up effectiveness studies for psychopharmacological treatment [ 5 ]. Medica- tion trials have been performed with various medications and aimed at different target symptoms. Most trials are open-label studies and case reports, and there is only a limited number of randomised control trials (RCTs) [ 69 , 110 ]. Risperidone has been demonstrated to be beneficial for irritability, repetitive behaviours and aggression, but a significant effect on social-communicative features has not been demonstrated [ 93 ]. Other antipsychotic drugs are used for similar behaviour, but research-based evidence of their effectiveness is lacking. Considering the possible long-term endocrine and metabolic side effects of classic and second- generation antipsychotics [ 3 , 35 , 42 , 99 ], these should be used with great care in children with ASD. Preliminary recommendations propose to monitor every three months during the first year of life and then annually the weight, height, blood pressure and body mass index (BMI), fasting glycaemia and lipidaemia, and checking for possible effects of hyperprolactinaemia [35 ]. Selective serotonin reuptake inhibitors (SSRIs) are regularly used in patients with ASD, both for depressive disorder and for compulsive behaviour. Their use in children has been much debated, as children may be at higher risk for behavioural activation and disinhibition, and the risk may be even greater in children with ASD [ 127 ], while evidence of therapeutic effects in

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this group is limited [ 79 ]. On hypothetical grounds, it has been proposed that SSRIs may modify key neuro- developmental processes in very young children with ASD [ 19 ], but there is no research to support this. More and more often, psycho-stimulants are being used for comorbid ADHD in ASD [ 48 ], and there are no particular contra- indications. It has been suggested that the required dosage of methylphenidate in ASD+ADHD is lower than in ADHD.

Other medical treatments

Mostly based on hypotheses on the pathogenesis and incidental observations, a host of novel therapies have been developed. A comprehensive and critical review can be found in Levy and Hyman s paper [ 84 ]. Amongst the proposed treatments are elimination diets, dietary supple- ments and vitamins, treatments targetting the immune system, steroids, antifungal agents to reduce intestinal candida overgrowth and chelating agents. Rigorous effect studies have not been performed for most of these therapies, and when they have been performed, have rather demonstrated the lack of effect, as famously demonstrated in the secretin case: the incidental observation that the core symptoms of autism improved significantly in three children after secretin perfusion [64 ] was not substantiated in 12 out of 13 placebo-controlled trials [ 46 ]. Nevertheless, so-called complementary and alternative medicine (CAM) have gained a large market share in the treatment of autism and often receive more attention in the media than scientifically proven treatments [117 ]. In the USA, almost three quarters of children with ASDs receive CAMs [ 62 ] in combination with more traditional treatments. Financial limitations may push parents to opt for CAMs only. Considering the potential side effects of some of the above-mentioned treatments, e.g. side effects of antifungal agents or steroids, or complications of strict elimination diets in growing children, many of these treatments are not as harmless as parents like to think. On the other hand, many children with ASD have unusual somatic character- istics and complaints, e.g. a higher prevalence of food hypersensitivity [ 90 ], which deserve appropriate treatment. Consequently, physicians cannot just discard the somatic questions that parents may have about their child with ASD, stating that ASD is a disorder solely affecting brain development.

Conclusions

The prevalence of autism spectrum disorder (ASD) seems to explode, with current estimates being around 1/160 people, a 25-fold increase compared with 30 years ago. The increase is mainly due to improving knowledge about the

clinical picture, the broadening of diagnostic criteria and the increase of diagnostic capacity. A real secular increase is at most low. Though the clinical increase is still below the scientific prevalence level, it exceeds existing diagnos- tic and therapeutic capacity in many countries. Non- psychiatric physicians are confronted with diagnostic and management questions for this group. Effective guidelines have been developed, e.g. by the American Academy of Pediatrics. So far, there is no comprehensive theory on the neurobiology of ASD, apart from the general insight that it behaves as a complex disorder, with heterogeneous aetiologies and effects on brain and cognition. One promising hypothesis that links a number of genetic and neurobiological findings is that of anomalies in brain connectivity. If many genes are involved, it is possible that other systems of the organism are affected by the same genes, e.g. the immune system and the gastro-intestinal (GI) tract. Anomalies without much clinical relevance have been found in the immune system, and an array of GI complaints have been described, amongst which gastro-oesophageal reflux disorder (GERD) is perhaps the most relevant, in particular in children who are limited in communicating physical discomfort. As there is no definite aetiological theory, there are no comprehensive guidelines for aetiological investigations, and these should primarily be guided by history and clinical examination. Only the hearing test in young children and high-resolution karyotype and DNA for fragile-X are recommended in all children. To focus additional genetic testing, examination by a clinical geneticist is recommen- ded. Early detection is a particular challenge for genetic and neurobiological research in autism. Though the genetic complexity makes it unlikely that a simple test with good screening properties will ever be found, current findings suggest that, in the coming years, micro-array technology will allow the prediction of the risk level in specific populations, e.g. infant siblings of children with ASD. At this stage, there is only evidence of small environmental effects in the pathogenesis of ASD, but in the coming years, growing insight in both the small-scale epidemiology and in the neurobiology of ASD may lead to the discovery of gene environment interactions, which will be very helpful in accepting or discarding some of the hypotheses about environmental factors and proposed alternative therapies and elimination diets. Amongst treatments at the behaviour level, approaches stimulating communication skills at an age as early as possible seem very promising besides older approaches based on adaptation of the environment, such as Treatment and Education of Autistic and related Communication- handicapped Children (TEACCH). However, the number of effect studies of behavioural treatments is limited and

handicapped Children (TEACCH). However, the number of effect studies of behavioural treatments is limited and

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clinicians have to adopt heuristic thinking to evaluate the possible benefits of particular therapies. The absence of a robust aetiological theory, the purely symptomatic effect of psychotropic drugs, their side effects, and the limitations of behavioural treatments may boost the hotchpotch of so- called complementary and alternative treatments towards which desperate parents have a tendency to turn. Though most physicians are not so tempted to read the alternative literature, a basic knowledge of it is essential in order to answer parents questions and help them differentiate between what s really not recommendable and what might be acceptable, even if it is not evidence based.

Acknowledgements This research was supported by the Clinical Research Fund of the University Hospital Leuven and by the Flanders Fund for Scientific Research (grant ZKB5798).

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