Acta Psychiatr Scand 2000: 102: 321330 Printed in UK.

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ACTA PSYCHIATRICA SCANDINAVICA ISSN 0001-690X

Review article

Autism and Asperger syndrome: coexistence with other clinical disorders

Gillberg C, Billstedt E. Autism and Asperger syndrome: coexistence with other clinical disorders. Acta Psychiatr Scand 2000: 102: 321330. # Munksgaard 2000. Objective: To provide a clinically useful analysis of the extent to which autism and Asperger syndrome coexist with other disorders. Method: Selective review of the literature detailing data pertaining to symptoms and disorders sometimes encountered in connection with autism or Asperger syndrome. Results: A large number of medical conditions, psychiatric disorders and behavioural and motor dyscontrol symptoms are associated with autism and Asperger syndrome. Conclusion: Comorbidity is to be expected in autism spectrum disorders directly or indirectly. Comorbid conditions may be markers for underlying pathophysiology and suggest a more varied treatment approach. There is a great need for in-depth research into this area, meaning that the exclusion criteria of current diagnostic manuals, i.e. those that rule out a diagnosis of autism in some disorders, and a diagnosis of certain other disorders in autism may have to be revised.

C. Gillberg, E. Billstedt
Department of Child and Adolescent Psychiatry, teborg, Sweden University of Go

Key words: Asperger syndrome; childhood autism; comorbidity Christopher Gillberg, Department of Child and teborg University, Annedals Adolescent Psychiatry, Go teborg, Sweden Clinics, S-413 45 Go Accepted for publication April 17, 2000

Introduction

Childhood autism (`Kanner syndrome') is a neurodevelopmental disorder, which is dened on behavioural criteria reecting abnormal development of social interaction, communication and imagination (13). It is part of a wider spectrum of disorders, which includes autistic psychopathy (`Asperger syndrome') (4, 5); childhood disintegrative disorder (`Heller syndrome') (2, 6), and autistic-like conditions (`atypical autism', `pervasive developmental disorder not otherwise specied') (2, 7, 8). Once believed to be an extremely rare disorder affecting 24 in 10 000 children (9), it is now becoming generally agreed that the autism spectrum disorders (Kanner syndrome included) affect at least half a per cent of the general population of children (10). There is growing acceptance that autism is not such a rare condition with precise and indisputable boundaries. It has also become clear that, in children and adults diagnosed in the autism spectrum, there are often other symptoms and disorders, not accounted for by the autism spectrum diagnosis itself. Thus, there are (1) a number of specic and unspecic `medical' diagnoses that are often made

alongside the diagnosis of autism, (2) a number of overlapping/comorbid behavioural syndromes that often occur both in classic autism/Kanner syndrome and in more high-functioning conditions including Asperger syndrome and, nally, (3) a number of overlapping/comorbid symptoms that do not by themselves amount to the status of `disorder diagnosis'. The issue of `comorbidity' is slightly contentious in that it is not always obvious what is inferred by the term. Problems/disorders `comorbid' with a given condition could be (i) coincidental, (b) causally directly related, one condition leading to the other, or (c) causally indirectly related, another underlying condition/impairment leading both to the core problem and the comorbid disorder (s). The term `overlapping conditions' may be more neutral in that it only infers that there may be overlap at the supercial level with no links to hypothetical etiology. The present paper deals with this issue by selectively reviewing the types and scope of clinically important coexisting problems in autism and Asperger syndrome. A section towards the end of 321

Gillberg and Billstedt the paper attempts to address the issue of the meaning of the ndings, both in terms of how autism should be theoretically conceptualized and what they suggest in the way of clinical diagnosis, workup and interventions.
Brief overview of coexistence with other disorders

The `medical diagnoses' that are often associated with autism can be subdivided into those that are unspecic and those that are rather more specic. In the former subgroup, mental retardation, epilepsy, speech and language disorders, hearing decits and visual impairments are the most common in Kanner syndrome. Motor disorders (DCD/Developmental Coordination Disorder, clumsiness, abnormal gait patterns, catatonic features) are also relatively common in Asperger syndrome, but otherwise the other `unspecic medical diagnoses' are rarely encountered in typical cases of Asperger syndrome. The specic medical diagnoses include some 50 different conditions, e.g. tuberous sclerosis, Angelman syndrome and Moebius syndrome, all of which have been shown by several different studies to be sometimes comorbid with autism or Asperger syndrome, and which have relatively large subgroups with associated autism/Asperger syndrome or other variants of severe autistic symptomatology. These more specic diagnoses are often, although by no means always, genetically determined disorders, many of which have identiable aetiologies. The behavioural and motor dyscontrol syndromes that are often overlapping or comorbid with autism also appear to be very common in Asperger syndrome, even though, for some conditions, the available evidence is less compelling for the latter syndrome, due mainly to the fact that less research has been published in respect of this syndrome than with regard to Kanner syndrome. Common overlapping syndromes include attentiondecit/hyperactivity disorder (ADHD), decits in attention, motor control and perception (DAMP), DCD, and Tourette syndrome. The behavioural and emotional symptoms commonly encountered in autism spectrum disorders, but which are currently not considered part of the set of diagnostic criteria, comprise sleep problems, abnormal sensory responses and attention decits and symptoms of abnormal activity levels.
Coexistence of autism and medical diagnoses Unspecic medical diagnoses

a fairly non-controversial statement, but one which would have to be revised were Asperger syndrome to be accepted as the most high-functioning variant of autism. Several recent studies have shown that cases clinically perceived as having Asperger syndrome (even Hans Asperger's own original cases) would be diagnosed as autistic disorder/childhood autism under the DSM-IV/ICD-10 (12, 13). Given that Asperger syndrome is much more common than autism and since there is usually no asscociated mental retardation many more cases of `nonretarded autism' would be identied, and hence the relative proportion of mental retardation in autism reduced drastically, perhaps even to under 20% (14). Epilepsy occurs in about 30% of all children with Kanner syndrome (5), and at much lower rates although possibly raised compared to the general population in Asperger syndrome. Speech and language and motor control peculiarities are common in Asperger syndrome, even though they are not highlighted as diagnostic criteria in the ICD or DSM. They are, however, included in one of the most often-used diagnostic manuals in the eld (15). Motor problems are also probably very common in autism (16), but the stereotype of the agile and beautiful individual with autism has possibly precluded systematic research in the eld. There has been considerable debate as to the separation of `semantic-pragmatic disorder' and `non-verbal learning disability' from high-functioning autism spectrum disorders (17, 18). Lowfunctioning individuals with autism are often mute (9). However, in the vast majority of cases, this is not caused by dysphasia (17), but is due probably to the underlying lack of an understanding of the meaning of communication (9, 11). Hearing impairment is much more common in autism than in the general population (19). About 1020% of all classic cases have moderatesevere or profound hearing decits. Severe visual impairment, including blindness, probably occurs at a rate well above that expected in the general population. Retinopathy of prematurity (ROP) is almost denitely over-represented in populations suffering from autism, and ROP carries an extremely high risk of autistic disorder (about one in every two cases) (20).
Specic medical diagnoses

More well-dened eponymous conditions affect about one in four of all children with autism in general population samples (21), and about one in eight in children referred to autism clinics (22). Tuberous sclerosis complex. One to three to one in ve of all children with tuberous sclerosis meet

Mental retardation occurs in 80% of all children with classic autism/Kanner syndrome (3, 11). This is 322

Autism and Asperger syndrome comorbidity full criteria for autism (2325). Those with early symptomatic tuberous sclerosis, i.e. those with symptoms of the disorder before 3 years of age, may meet criteria for autistic disorder even more often, at a rate of 5060% (26). Extrapolating from general population prevalence data on tuberous sclerosis and autism these ndings indicate that 29% of all autism cases are associated with tuberous sclerosis. This proportion would be higher if autism cases with mental retardation only were considered, and much higher still if a sample of individuals with the combination of autism, mental retardation and early onset epilepsy was being worked-up. It appears that the location of the tubers (temporofrontal in particular) are linked to autistic symptomatology in tuberous sclerosis (27). Tuberous sclerois exists in at least two variants TSC2 and TSC1. TCS2 is located on chromosome 16p13.3 (encoding for the tuberin protein which appears to have growth regulating properties) and chromosome 9q34 (which encodes hamartin, whose cellular functions are still unknown). It is of interest that one of the autism susceptibility genes identied by several different research groups is in the TSC2 region (28). Other neurocutaneous syndromes. Both neurobromatosis type 1 (NF1) and hypomelanosis of Ito have been suggested to be associated with autism. In the case of NF1, a population study found 6% of cases with autism/atypical autism also met criteria for this diagnosis (29). NF1 is located on chromosome 17. NF2, leading to vestibular schwannomas and other tumours, has not yet been suggested to be associated with autism. NF2 is located on chromosme 22. Hypomelanosis of Ito has been reported in a considerable number of cases with autism spectrum disorders (30, 31), mainly Asperger syndrome and atypical autism. In a series of 76 patients with hypomelanosis of Ito, 10% had marked autistic features (32). The aetiology of hypomelanosis of Ito remains obscure. Fragile X syndrome. About one in three of all males with the full fragile X mutation show marked autistic features, and many of these meet full criteria for autism early in life (33). Conversely, 210% of all autism cases are associated with the fragile X syndrome (21, 34). The fragile X syndrome has been shown to be associated with executive function decits suggesting frontal lobe dysfunction (35). The frontal lobes have been implicated in the pathogenesis of autism in many recent reports, including a PET-scan study of Asperger syndrome (36). Partial tetrasomy 15q11.13. There is growing agreement that abnormality on chromosome 15q, particularly the condition now known as partial tetrasomy 15q11.13, is associated with autistic symptomatology (37). This area on chromosome 15 is abnormal in two behavioural phenotype syndromes, namely PraderWilli syndrome and Angelman syndrome. The former of these is not associated with autism, whereas the other is strongly linked to autistic symptomatology. Interestingly, both these syndromes comprise rigid, stereotyped and repetitive behaviour patterns, which are also hallmarks of disorders in the autism spectrum. Other chromosomal disorders. Most of the human chromosomes have been implicated in the pathogenesis of autism. However, a recent review of all chromosomal studies in autism (38) suggests that susceptibility genes for autism would be most likely to be found on chromosome 15 and on the X chromosome, the two chromosomes that have been most consistently reported to show abnormality in the eld of autism spectrum disorders. Rett syndrome complex. For obscure reasons, Rett syndrome has become listed as a particular form of an autism spectrum disorder in the ICD-10 and DSM-IV. It is categorized there as one of the pervasive developmental disorders (PDDs). Rett syndrome is conceptually similar to other neurological disorders/syndromes in that it has a relatively large subgroup with severe autistic symptomatology. However, not all individuals with Rett syndrome have any autistic symptoms at all, and tuberous sclerosis, with a possibly stronger link to autistic symptoms, is not grouped as a PDD. Nevertheless, it is important to make note of the fact that young girls developing autistic symptoms should be suspected of suffering from Rett syndrome. It is also important to be aware that there are preserved speech cases in the Rett syndrome -vis complex (39), making differential diagnosis vis-a autism sometimes very difcult. Rett syndrome has recently been shown to be strongly associated with a gene coding for the protein MECp2, which is located on chromosome Xq28. Because of the considerable overlap of autism and Rett syndrome in terms of symptomatology at some stages of development, this discovery might provide a clue to one of the locations for autism susceptibility genes. 323

Gillberg and Billstedt Moebius syndrome. Several different studies have shown a considerable subgroup of patients with Moebius syndrome (congenital, bilateral facial nerve palsies usually due to abnormalities in the brainstem) has an associated autistic disorder (40). The connection with Moebius syndrome suggests brain stem pathology in some cases of autism. Thalidomide syndrome. In a study of all 100 Swedish victims of the thalidomide disaster, at least 4% met full criteria for autistic disorder (41). This nding is also suggestive of early rst trimester brain stem lesions as one possible pathogenetic mechanism in autism. Other medical conditions. Many other conditions than those listed in the foregoing have been reported to be associated with autism. They include fetal alcohol syndrome (42), rubella embryopathy (43) and metabolic disorders, and have been reviewed in detail by Gillberg and Coleman (21).
Behavioural and motor control problems that often coexist with autism and Asperger syndrome

Many individuals with syndromes dened on the basis of deviant behaviour or motor dyscontrol also meet all or most of the symptom criteria for diagnosing autistic disorder or Asperger syndrome. The most common of these appear to be ADHD and Tourette syndrome, but many other more or less well-dened behavioural and motor dyscontrol syndromes also have subgroups that meet most or all of the criteria for Kanner syndrome or Asperger syndrome. Some individuals with autism spectrum disorders have symptoms of specic behavioural syndromes that do not amount to the level of cut-off for diagnosis. There is also a host of non-core symtpoms associated with autism, problems that may be very marked and handicapping but that are not included among the diagnostic criteria for autism spectrum disorders.
ADHD

Asperger syndrome in several different publications (44, 45). In a preliminary report they described the occurrence of psychiatric disorders in a series of 35 patients with Asperger syndrome diagnosed according to the ICD-10/DSM-IV criteria. Two-thirds of the patients had an additional psychiatric disorder. Children were most likely to suffer from ADHD, while depression was the most common diagnosis in adolescents and adults (see further under Depression). Recent neuropsychological studies (46, 47) have demonstrated that high-functioning autism and Asperger syndrome are characterized by similar types and degrees of attention decits that are seen most clearly in children with ADHD. Even though these studies did not formally diagnose the children with autism or Asperger syndrome as having ADHD, it is clear that attention decits are very common, if not universal, in disorders in the autism spectrum. Children with autism can be hyperactive or hypoactive. Only relatively few are normally active in infancy and the preschool period. There is often a characteristic trajectory of development in this respect with hyperactivity in the preschool years followed by more normoactive behaviour in the early school years and a tendency to hypoactivity from early adolescence. Extreme degrees of hyperactivity are often encountered in individuals with autism and autisticlike conditions who suffer from the fragile-X syndrome (33). This is also true in many cases of autism spectrum disorders combined with tuberous sclerosis (23, 25). The hyperactivity is usually most pronounced in the rst 10 years of life, and may be linked to severe bouts of aggression and destructive behaviours. These ndings suggest that there may be meaningful subgroups within the autism spectrum that are better characterized by their comorbidity than their diagnostic status within the autism spectrum.
DAMP

Very few studies have looked systematically at the evidence linking autism and attention decits (including ADHD). Some of the failure to address this important comorbidity issue can probably be attributed to the specication in the diagnostic manuals that autism and ADHD should not be diagnosed conjointly in any individual patient. Mohammad Ghaziuddin and co-workers have reported on the comorbidity of autism and 324

The Scandinavian concept of DAMP, while not generally accepted outside Northern Europe, has been the subject of many empirical studies. DAMP is conceptualized as the combination of ADHD and motor-perceptual dysfunctions (now often referred to as developmental coordination disorder, or `DCD'). A relationship between DAMP and autistic-type behaviours was already noted in the rst longitudinal study of Swedish 7-year-olds with and without DAMP (48). In that study 1.2% of the general population had `severe DAMP' (comprising ADHD plus DCD plus perceptual problems plus speechlanguage problems). Slightly more than half

Autism and Asperger syndrome comorbidity of the children with severe DAMP also had some marked autistic features, i.e. they had the autism triad, but symptoms were less severe than in classic autism in at least one of the three relevant domains (social interaction, communication, imagination). Almost half of this proportion (of children with severe DAMP with autistic features) met full criteria for Asperger syndrome (15). Two other population studies of Swedish 7-year-olds have demonstrated a similar degree of comorbidity of DAMP with autistic features (49, 50).
DCD

Several other authors have noted a similar association (58, 59), and the present authors have come across several young individuals with autism/ Asperger syndrome and catatonia developing in adolescence.
Obsessive-compulsive behaviour problems

The type of motor co-ordination problems considered typical of Asperger syndrome (4) are also those that are typical of DCD (and hence of DAMP). Highly sophisticated analysis of home videotapes of the motor behaviours of infants who are later diagnosed as having the syndrome of autism has revealed consistent motor abnormalities, including abnormal turning-around behaviours and a `Moebius-like' facial motor performance (51). This provides another piece of evidence suggesting that brain stem dysfunction is important in the pathogenesis of autism.
Tics and Tourette syndrome

There are many similarities between the obsessive and compulsive phenomena of obsessive compulsive disorder (`OCD') and obsessive compulsive personality disorder (`OCPD') and the ritualistic and repetitive behaviours typical of both Kanner and Asperger syndromes (60). The symptomatology of OCPD, as outlined in the DSM-IV, is strikingly similar to that of autistic psycopathy as portrayed by Asperger (4).
Depression

Links between affective disorders and autism have been suggested for decades (3). Depression is overrepresented in close relatives of individuals suffering from autism (61). It is common in children and adolescents with autism (44), and it has been reported to be very common in Asperger syndrome (45, 62, 63).
Eating disorders

It is only quite recently that the prevalence of tics in autism has become the subject of empirical study. The relationship of Asperger syndrome and tics, on the other hand, has been noted for quite some time, and has been interpreted either as a spurious nding or a marker for better outcome, both of which now appear to be mistaken. In a study of young people with autism, 8% were found to have comorbid Tourette syndrome (52). Several reports (5355) have documented the cooccurrence of Tourette syndrome and Asperger syndrome. Some authors have taken this type of comorbidity as a predictor of better outcome in autism, but the evidence is not yet sufcient to warrant such a conclusion. In a Swedish population study, 20% of all school-age children with denite Asperger syndrome also met full criteria for Tourette syndrome, and a full 80% had tics of one kind or another (55). In another Swedish population study, 10% of children with Tourette syndrome also met full criteria for Asperger syndrome (56).
Catatonia movement disorder

Lorna Wing has long argued that some relatively high-functioning individuals with autism develop catatonia in late childhoodearly adult life (57).

Autism was reported in a case of anorexia nervosa 20 years ago (64). Several cases of anorexia nervosa and autism occurring in the same families were described by Gillberg (65) and later by Comings (66). In a controlled follow-up study of representative cases of anorexia nervosa, 18% had an autism spectrum disorder (4% autistic disorder, 6% Asperger syndrome and 8% atypical autism) both at the time of onset of the eating disorder (around 15 years of age) and 5 and 10 years later (67). A German study showed the rate of underweight and eating disorders to be much increased in Asperger syndrome/schizoid personality disorder (68). Problems with eating including particular food refusal, food fads, pica, hoarding, overeating and various degrees of anorectic behaviours, including complete food refusal and compulsive ordering of food on the plate are extremely common in autism. Some children with autism appear to prefer only soft foods and may have difculty chewing (or rather knowing that they are expected to chew). Others prefer only solid foods and appear nauseated when expected to eat certain minced foods. It is very common for children with autism to accept only pasta and French-fries. Low-functioning individuals may `eat' anything within reach, including 325

Gillberg and Billstedt pieces of papers, cigarettes, owers and even needles and pins.
Selective mutism

Case reports of autism/Asperger syndrome/schizoid personality disorder in children have drawn attention to the possible comorbidity and familial links of autism spectrum disorders and selective mutism (5, 69, 70). In a population study of selective mutism, Kopp and Gillberg (71) found that one (a girl) out of ve school age children with selective mutism also met full diagnostic criteria for Asperger syndrome.
Childhood schizophrenia

Originally believed to be childhood schizophrenia, autism has long been separated from schizophrenia, and is considered by most authorities in the eld to have little, if anything, to do with this disorder. Nevertheless, there is suggestive evidence that children diagnosed with schizophrenia often have an early history indicating an autism spectrum disorder (72).
Adolescent onset psychosis

Fluctuating activity levels are common throughout the lifespan of some individuals with autism, and there is sometimes concern that the individual might be suffering from manic-depressive type mood swings or outright bipolar disorder. In highfunctioning patients with autism it has been well documented that there is an increased risk of bipolar disorder, both in the patients themselves and their close relatives (75). Asperger syndrome and other high-functioning autism spectrum disorders are sometimes found in young adult forensic psychiatric patients, if workup is performed with a particular view to nding psychiatric and developmental disorders with onset in childhood (76). There is also some limited evidence that Asperger syndrome may be overrepresented among mentally ill convicted violent offenders (77).
Abnormal responses to sensory stimuli

Among 61 individuals presenting with `psychotic' symptoms (hallucinations, delusions, thought disorder, mania, confusion) in adolescence (1319 years), 5% had a prior diagnosis of Kanner syndrome (infantile autism) or Heller syndrome (disintegrative psychosis) (73). These were cases originally believed to have a relatively good prognosis. The autism spectrum diagnoses had been made prior to age 5 years, and by age 10 years, the children were doing remarkably well given the original diagnostic categorization. However, in teenage, they suddenly, an unexpectedly developed orid psychotic symptoms.
Personality disorders and psychiatric disorders usually rst diagnosed in adolescence or adult life

Judging from the diagnostic criteria for many of the personality disorders in the DSM-IV, particularly those grouped as clusters A and C, there should be a considerable degree of overlap between Asperger syndrome and such conditions. No study has looked specically at this type of overlap, but indirect data from a follow-up study of eating disorders (67) suggest that the overlap between Asperger syndrome and OCPD may be very marked. Other personality disorder criteria likely to be met by many individuals with Asperger syndrome include those of paranoid, schizoid (67) and schizotypal personality disorder (74). 326

In a prospective study of children with autism seen before their third birthday, `abnormal responses to sensory stimuli' was the class of symptoms, which most clearly distinguished autism from mental retardation (78). Ornitz (79) reported similar ndings. Of these symptoms, an abnormal response to sound may be thought of as the most characteristic of all. The child who `acts deaf' and does not react at all when an explosion is unexpectedly heard nearby may moments later turn at the sound of a paper being removed from a chocolate (78). Many children with autism cover their ears to shut out even `ordinary' noise levels (11, 80). Abnormal responses to visual stimuli are present in a subgroup of young children with autism, who often give the impression of having difculty recognizing the things they see. Every now and then autism is mistaken for blindness. Some children with delayed visual maturation show many or all of the symptoms of autism (81). It is possible that some aspects of the abnormal gaze behaviour characteristic of so many cases with autism and Asperger syndrome reect underlying visual perceptual abnormalities (82). Abnormal reactions to touch, pain, heat or cold is often encountered in autism (3). Children with autism often want to smell people and objects (3). Clinical experience suggests that perceptions relating to auditory and tactile stimuli may be more impaired in autism than are perceptions of visual and, especially, olfactory stimuli. The two latter functions make their rst intracranial nerve connections at a higher level in the nervous system. A preference for proximal stimuli has also been experimentally evidenced in autism (83).

Autism and Asperger syndrome comorbidity Although abnormal sensory responses in autism are regarded by many as `primary' and in their view should therefore be included among the diagnostic criteria, the most inuential diagnostic manuals do not do this. Nevertheless, most authorities agree that for instance `undue sensitivity to sound' is an extremely common feature in autism and that it differentiates autism from, for instance, dysphasia (11, 80).
Abnormal sleep patterns

Sleep patterns are abnormal in autism in a majority of all cases (84). They may be most striking in infancy and the rst few years of life, when the child may keep the whole family awake by crying, but may sometimes continue right through to adulthood. It is not uncommon for major sleep problems to be the rst obvious outward sign that something is seriously amiss in an infant who receive a diagnosis of autism only years later.
Aggression

Aggressive behaviours are common in autism at all ages, but perhaps particularly in the adolescent and young adult group (85). It is possibly overrepresented in Asperger syndrome also (86). The aggressive acts can take on frightening proportions and can lead to the requirement for heavy medication or treatment in high-security wards. Nevertheless, it is important to note that the majority of individuals with autism spectrum disorders are not aggressive and that it is rare for really dangerous situations to develop, even in the group that exhibits severely aggressive behaviours.
Self-injury

Self-injurious behaviours (SIBs) are said to abound particularly in children with the combination of autism and mental retardation (87). However, SIB is common also in individuals with high-functioning autism. Some of the most common manifestations of SIB are head-banging, wrist- or knuckle-biting, chin-knocking, cheek-smacking, eye-poking, hairtearing and clawing.
Concluding remarks Implications for clinical practice in the everyday care of individuals in the autism spectrum

It is already clear that comorbidity is common, indeed the rule, in autism and, albeit less well documented, in Asperger syndrome. Mental retardation occurs in about three-quarters of classical

cases of autism. An associated medical disorder, such as tuberous sclerosis, a metabolic or chromosomal disorder, is present in 1025% of cases depending on whether specialized clinic or community samples are being studied. In addition, epilepsy, hearing and visual impairments are very common. Such problems are relatively rare in Asperger syndrome. However, with regard to additional neuropsychiatric problems, such as ADHD, Tourette syndrome and other tic disorders, both autism and Asperger syndrome show very high rates of comorbidity. This may have important consequences for treatment. There is little, if any, evidence that individuals with autism spectrum disorders respond less well to treatments for these comorbid problems than do those without a diagnosis in the autism spectrum. The implications are that: (a) comorbidity is to be expected whenever a diagnosis of autism or Asperger syndrome is made, and (b) the exclusion criteria of the DSM and ICD, i.e. those that rule out a diagnosis of autism in another disorder and a diagnosis of another disorder in autism, may have to be disregarded. There is a risk that children who do not receive diagnoses of all their various types of problems may be withdrawn both from general services, such as proper schooling, if ADHD is the only diagnosis made in a case with both ADHD and autism and specic treatments such as stimulant medication if autism is the only diagnosis made in a case with both autism and ADHD. The DSM and ICD criteria are based on diagnostic algorithms according to relatively strict hierarchical rules. The underlying assumption has often been that certain disorders are more `severe', `basic' or `pure' than others. This has clearly been the case in the eld of autism, which has long been hailed as the `best dened' of all child psychiatric disorders (9, 11, 22). The algorithms have been historically important, and provided a framework for studying `purer' forms of disorders, allowing the beginning of an understanding of the underpinnings of at least some clinical syndromes. However, adhering rigidly to the strict exclusion criteria, in the face of mounting clinical evidence that they do not reect the problem proles shown by real-life patients, presents major clinical problems for affected individuals and their families (52). It has sometimes precluded the development both of realistic clinical services and more meaningful pathogenetic research. The problems associated with insistence on ruling out certain diagnostic possibilities are clearly reected in the ICD-10 section on autism. According to the strict operational rules, childhood autism should be diagnosed in cases showing the 327

Gillberg and Billstedt typical autism triad before age 36 months. However, other childhood disintegrative disorders can equally be diagnosed if the child shows this symptom triad from the age of 25 months. For both disorders there is a criterion stating that symptoms should not be `attributable to the other varieties of pervasive developmental disorder'. So how is one to diagnose children with symptom onset between 25 and 36 months? A case in point of the absurd situation that sometimes arises because of strict exclusion criteria in the DSM-IV is the category of Asperger's disorder in that manual. None of Asperger's own cases meet the diagnostic criteria for Asperger's disorder (12)! These examples highlight the need for more extensive participation of clinical researchers and clinicians (including as chairs) of the task forces of the DSM and ICD. of individuals diagnosed as having childhood autism (14). Fourthly, there may be lessons to be learnt from more intense study of some of the specic medical disorders. For instance, in tuberous sclerosis, it appears that autistic symptoms are much more likely to arise when there is temporal lobe (and temporofrontal) afiction as compared with when these brain areas are unscathed (27). However, there is also the possibility that tuberous sclerosis, with at least two different gene locations on chromosomes 9 and 16 increases the risk of autism specically through gene effects. Two recent genome scan studies of sib-pairs with autism have implicated the tuberous sclerosis chromosome 16 area as a possible location for one of the autism susceptibility genes. The connection between thalidomide embryopathy and Moebius syndrome on one hand and autism on the other hand has implicated early rst trimester brain stem insult as one possible mechanism. The studies of these syndromes (40) have also implicated precise developmental timing windows and specic brain stem areas in the pathogenesis of at least some autism cases. The discovery of infant motor control abnormalities in autism (51), and the suggestion that the typical `Moebius mouth' may be present in infancy in autism, provide further support for the notion of specic brain stem abnormalities in the pathogenetic chain of events. Finally, the realization that autism is not a often encountered in the shape of a `pure' disorder, which one can easily separate out from all other conditions, should make obvious the need of new approaches in research. Studies of large general population samples where comorbidity patterns can be analysed without bias should receive high priority. Patterns of referral and atypical individual characteristics need to be addressed in all studies of selected clinical samples. Small-scale `high-tech' studies (e.g. neuroimaging studies) should include `pure' cases (if such cases exist at all) and cases with various patterns of comorbidity. Also, as in the clinical setting, the exclusion criteria of the DSM and ICD, may need to be disregarded or dealt with in other ways.
References
1. KANNER L, EISENBERG L. Early infantile autism: 19431955. Am J Orthopsychiatry 1956;26:5565. 2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edn. Washington, DC: American Psychiatric Association, 1994. 3. WING L. Autism spectrum disorder (Editorial). Br Med J 1996;312:327328. 4. ASPERGER H. Die autistischen Psychopathen im Kindesalter. Arch Psychiatr Nervenkrank 1944;117:76136.

Implications for research on underlying mechanisms in autism and Asperger syndrome

The overlap/comorbidity encountered in disorders on the autism spectrum has several implications for the understanding of pathogenesis in autism. First, the extent and pattern of overlap with other disorders and symptoms suggest that it would be unlikely that a unique (and pathognomonic) set of aetiological factors will be identied that pertain to autism and autism only. Secondly, the overlap with symptoms and disorders involving attention decits and tics implicate dysfunction of the dopamine system in the brain in autism spectrum disorders. There is some evidence that genes involved in the regulation of dopamine functioning may be abnormal in ADHD (8891), and it has long been suggested, e.g. on the basis of the positive symptomatic effects of central stimulants, that dopamine dysfunction might be at the root of ADHD. Several lines of evidence, e.g. the reduction of tics by dopamine blockers, implicate the dopamine system also in Tourette's and other tic disorders (92, 93). There are also many other indirect leads linking autism with dopamine dysfunction. These include abnormal cerebrospinal uid levels of dopamine breakdown products, rigid and catatonic motor behaviours, and the abundance of motor stereotypies usually encountered in classic variants of childhood autism (14). Thirdly, the overlap with symptoms and syndromes involving obsessions and compulsions (60) suggest that the serotonin system may also be dysfunctional in disorders in the autism spectrum. Again, there are other indirect links between autism and serotonin dysfunction, most notably the robust nding of serotonin hyperfunction in about a third 328

Autism and Asperger syndrome comorbidity

5. GILLBERG C. Clinical and neurobiological aspects of Asperger syndrome in six family studies. In: FRITH U, ed. Autism and Asperger syndrome. Cambridge: Cambridge University Press, 1991:122146. 6. VOLKMAR FR. Childhood disintegrative disorder: issues for DSM-IV. J Autism Dev Disord 1992;22:625642. 7. STEFFENBURG S, GILLBERG C. Autism and autistic-like conditions in Swedish rural and urban areas: a population study. Br J Psychiatry 1986;149:8187. 8. World Health Organization. The ICD-10 classication of mental and behavioural disorders. Diagnostic criteria for research. Geneva: World Health Organization, 1993. 9. LORD C, RUTTER M. Autism and pervasive developmental disorders. In: RUTTER M, TAYLOR E, HERSOV L, eds. Child and adolescent psychiatry. Modern approaches, 3rd edn. Oxford: Blackwell Scientic Publications, 1994:569593. 10. GILLBERG C, WING L. Autism: not an extremely rare disorder. Acta Psychiatr Scand 1999;99:399406. 11. RUTTER M. Cognitive decits in the pathogenesis of autism. J Child Psychol Psychiatry 1983;24:513531. 12. MILLER JN, OZONOFF S. Did Asperger's cases have Asperger disorders? A research note. J Child Psychol Psychiatry 1997; 38:247251. 13. LEEKAM S, LIBBY S, WING L, GOULD J, GILLBERG C. Comparison of ICD-10 and Gillberg's criteria for Asperger syndrome. Autism 2000;4:1128. 14. GILLBERG C. The Emanuel Miller Memorial Lecture 1991. Autism and autistic-like conditions: subclasses among disorders of empathy. J Child Psychol Psychiatry 1992;33: 813842. 15. GILLBERG IC, GILLBERG C. Asperger syndrome some epidemiological considerations: a research note. J Child Psychol Psychiatry 1989;30:631638. 16. DEMYER MK, ALPERN GD, BARTON S et al. Imitation in autistic, early schizophrenic, and non-psychotic subnormal children. J Autism Child Schizophr 1972;2:264287. 17. RAPIN I, ALLEN D. Developmental language disorders: nosologic considerations. In: KIRK U, ed. Neuropsychology of language reading and spelling. New York: Academic Press, 1983. 18. BISHOP DVM. Autism, Asperger's syndrome and semanticpragmatic disorders. Where are the boundaries? Br J Disord Commun 1989;24:107121. M M, NORDIN V, GILLBERG C. 19. ROSENHALL U, SANDSTRO Autism and hearing loss. J Autism Dev Disord 1999; 29:349357. 20. EK U, FERNELL E, JACOBSSON L, GILLBERG C. Relation between blindness due to retinopathy of prematurity and autistic spectrum disorders: a population-based study. Dev Med Child Neurol 1998;40:297301. 21. GILLBERG C, COLEMAN M. Autism and medical disorders. A review of the literature. Dev Med Child Neurol 1996; 38:191202. 22. RUTTER M, BAILEY A, BOLTON P, LE COUTEUR A. Autism and known medical conditions: myth and substance. J Child Psychol Psychiatry 1994;35:311322. 23. HUNT A, DENNIS J. Psychiatric disorder among children with tuberous sclerosis. Dev Med Child Neurol 1987;29:190198. 24. SMALLEY SL. Autism and tuberous sclerosis (Review). J Autism Dev Disord 1998;28:407414. 25. BAKER P, PIVEN J, SATO Y. Autism and tuberous sclerosis complex: prevalence and clinical features. J Autism Dev Disord 1998;4:279285. N G. Autistic behaviour 26. GILLBERG IC, GILLBERG C, AHLSE and attention decits in tuberous sclerosis. A populationbased study. Dev Med Child Neurol 1994;36:5056. 27. BOLTON PF, GRIFFITHS PD. Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet 1997;349:392395. PHILIPPE A, MARTINEZ M, GUILLORD-BATAILLE M et al. Genome-wide scan for autism susceptibility genes. Hum Mol Genet 1999;8:805812. GILLBERG C, FORSELL C. Childhood psychosis and neurobromatosis more than a coincidence? J Autism Dev Disord 1984;14:18. KEFELDT A, GILLBERG C. Hypomelanosis of Ito in three A cases with autism and autistic-like conditions. Dev Med Child Neurol 1991;33:737743. ZAPPELLA M. Hypomelanosis of Ito is common in autistic syndromes. Eur Child Adolesc Psychiatry 1992;1:170177. PASCUAL-CASTROVIEJO I, ROCHE C, MARTINEZ-BERMEJO A et al. Hypomelanosis of ITO. A study of 76 infantile cases. Brain Dev 1998;1:3643. TURK J. The fragile-X syndrome. On the way to a behavioural phenotype. Br J Psychiatry 1992;160:2435. HAGERMAN RJ. Chromosomes, genes and autism. In: GILLBERG C, ed. Diagnosis and treatment of autism. New York: Plenum Press, 1989:105132. SOBESKY WE, TAYLOR AK, PENNINGTON BF et al. Molecular/ clinical correlations in females with fragile X. Am J Med Gen 1996;64:340345. F, EHLERS S, FLETCHER P et al. `Theory of mind' in the HAPPE brain. Evidence from a PET scan study of Asperger syndrome. Neuroreport 1996;8:197201. M J et al. Autism GILLBERG C, STEFFENBURG S, WAHLSTRO associated with marker chromosome. J Am Acad Child Adolesc Psychiatry 1991;30:489494. GILLBERG C. Chromosomal disorders and autism. J Autism Dev Disord 1998;28:415425. ZAPPELLA M, GILLBERG C, EHLERS S. Rett syndrome variants? Preserved speech in 30 girls with autistic behavior and many features of Rett syndrome. J Autism Dev Disord 1998;28:519526. MLAND K, GILLBERG C, JOHANSSON M, MILLER MT, STRO WENTZ NILSSON E. The puzzle of autism: an ophthalmologic contribution. Trans Am Ophthalmol Soc 1998;96:369385. KERSTRO MLAND K, NORDIN V, MILLER M, A M B, STRO GILLBERG C. Autism in thalidomide embryopathy: a population study. Dev Med Child Neurol 1994;36:351356. ARONSON M, HAGBERG B, GILLBERG C. Attention decits and autistic spectrum problems in children exposed to alcohol during gestation: a follow-up study. Dev Med Child Neurol 1997;39:583587. CHESS S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr 1977;7:6881. GHAZIUDDIN M, GREDEN J. Depression in children with autism/pervasive developmental disorders: a casecontrol family history study. J Autism Dev Disord 1998;28:111 115. GHAZIUDDIN M, WEIDMER-MIKHAI E, GHAZIUDDIN N. Comorbidity of Asperger syndrome: a preliminary report. J Intellect Disabil Res 1998;42:279283. N A, GILLBERG C et al. Asperger syndrome, EHLERS S, NYDE autism and attention disorders: a comparative study of the cognitive prole of 120 children. J Child Psychol Psychiatry 1997;38:207217. N A, GILLBERG C, HJELMQUIST E, HEIMAN M. Executive NYDE function/attention in boys with Asperger syndrome, attention disorders and reading/writing disorder. Autism 1999;3:213228. GILLBERG C. Perceptual, motor and attentional decits in Swedish primary school children. Some child psychiatric aspects. J Child Psychol Psychiatry 1983;24:377403. LANDGREN M, PETTERSSON R, KJELLMAN B, GILLBERG C. ADHD, DAMP and other neurodevelopmental/neuropsy-

28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39.

40. 41. 42.

43. 44.

45. 46.

47.

48. 49.

329

Gillberg and Billstedt

chiatric disorders in six-year-old children. Epidemiology and comorbidity. Dev Med Child Neurol 1996;38:891906. B, GILLBERG C. Developmental co-ordination disKADESJO order in Swedish 7-year-olds. J Am Acad Child Adolesc Psychiatry 1999;38:820828. TEITELBAUM R, GLATMAN-FREEDMAN A, CHEN B et al. A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival. Proc Natl Acad Sci USA 1998;95: 1568815693. BARON-COHEN S, MORTIMORE C, MORIARTY J, IZAGUIRRE J, ROBERTSON M. The prevalence of Gilles de la Tourette's syndrome in children and adolescents with autism. J Child Psychol Psychiatry 1999;2:213218. KERBESHIAN J, BURD L. Case study: comorbidity among Tourette's syndrome, autistic disorder, and bipolar disorder. J Am Acad Child Adolesc Psychiatry 1996;35:681685. NASS R, GUTMAN R. Boys with Asperger's disorder, exceptional verbal intelligence, tics, and clumsiness. Dev Med Child Neurol 1997;39:691695. EHLERS S, GILLBERG C. The epidemiology of Asperger syndrome. A total population study. J Child Psychol Psychiatry 1993;34:13271350. B, GILLBERG C. Tourette's disorder: epidemiology KADESJO and comorbidity in primary school children. J Am Acad Child Adolesc Psychiatry 2000;39:548555. WING L, ATTWOOD A. Syndromes of autism and atypical development. In: COHEN DJ, DONNELLAN AM, eds. Handbook of autism and pervasive developmental disorders. New York: John Wiley & Sons, 1987:319. REALMUTO GM, AUGUST GJ. Catatonia in autistic disorder: a sign of comorbidity or variable expression? J Autism Dev Disord 1991;21:517528. DHOSSCHE D. Brief report: catatonia in autistic disorders. J Autism Dev Disord 1998;28:329331. HOLLANDER E. Treatment of obsessive-compulsive spectrum disorders with SSRIs. Br J Psychiatry 1998;173(Suppl. 35): 712. PIVEN J, PALMER P. Psychiatric disorder and the broad autism phenotype: evidence from a family study of multipleincidence autism families. Am J Psychiatry 1999;4:557563. WING L. Asperger's syndrome: a clinical account. Psychol Med 1981;11:115129. GILLBERG C. Asperger syndrome and high-functioning autism. Br J Psychiatry 1998;172:200209. STIVER RLS, DOBBINS JP. Treatment of atypical anorexia nervosa in public school: an autistic girl. J Autism Dev Disord 1980;10:6773. GILLBERG C. Are autism and anorexia nervosa related? [Letter]. Br J Psychiatry 1983;142:428. COMINGS DE. Tourette syndrome and human behaviour. Duarte, California: Hope Press:1990. STAM M. WENTZ NILSSON E, GILLBERG C, GILLBERG IC, RA Ten year follow-up of adolescent-onset anorexia nervosa: personality disorders. J Am Acad Child Adolesc Psychiatry 1999;38:16111616. HEBEBRAND J, HENNINGHAUSEN K, NAU S et al. Low body weight in male children and adolescents with schizoid personality disorder or Asperger's disorder. Acta Psychiatr Scand 1997;96:6467. WOLFF S, CHICK J. Schizoid personality in childhood: a controlled follow-up study. Psychol Med 1980;10:85100. BANKIER B, LENZ G, GUTIERREZ K, BACH M, KATSCHNIG H. A case of Asperger's syndrome rst diagnosed in adulthood. Psychopathology 1999;32:4346. KOPP S, GILLBERG C. Selective mutism: a population-based study: research note. J Child Psychol Psychiatry 1997;38: 257262. ASARNOW JR, BEN-MEIR S. Children with schizophrenia spectrum and depressive disorders: a comparative study of premorbid adjustment, onset pattern and severity of impairment. J Child Psychol Psychiatry 1988;29:477488. M J, FORSMAN A, HELLGREN L, GILLBERG C, WAHLSTRO GILLBERG IC. Teenage psychoses epidemiology, classication and reduced optimality in the pre-, peri- and neonatal periods. J Child Psychol Psychiatry 1986;27:8798. NAGY J, SZATMARI P. A chart review of schizotypal personality disorders in autism. J Autism Dev Disord 1986;16: 351367. DELONG GR, DWYER JT. Correlation of family history with specic autistic subgroups: Asperger's syndrome and bipolar affective disease. J Autism Dev Disord 1988;18: 593600. N A, JONSON C, GILLBERG SIPONMAA L, KRISTIANSSON M, NYDE C. Young forensic psychiatric patients: the role of child neuropsychiatric disorders. 1999, submitted. SCRAGG P, SHAH A. Prevalence of Asperger's syndrome in a secure hospital. Br J Psychiatry 1994;165:679682. GILLBERG C, EHLERS S, SCHAUMANN H et al. Autism under age 3 years: a clinical study of 28 cases referred for autistic symptoms in infancy. J Child Psychol Psychiatry 1990;31: 921934. ORNITZ E. Early symptoms of autism. Paper presented at Congress of the Federation of Societies of Biological Psychiatry, Jerusalem, April; 1989. RUTTER M. Diagnosis and denition of childhood autism. J Autism Child Schizophr 1978;8:139161. GOODMAN R, ASHBY L. Delayed visual maturation and autism. Dev Med Child Neurol 1990;32:814819. BARON-COHEN S. Mind blindness. An essay on autism and theory of mind. Cambridge: MIT Press, 1995. HERMELIN B, O'CONNOR N. Psychological experiments with autistic children. Oxford: Pergamon Press, 1970. RICHDALE AL, PRIOR MR. The sleep/wake rhythm in children with autism. Eur Child Adolesc Psychiatry 1995;4:175186. HORRIGAN JP, BARNHILL LJ. Does guanfacine trigger mania in children? J Child Adolesc Psychopharmacol 1998;8:149150. KOHN Y, FAHUM T, RATZON IG, APTER A. Aggression and sexual offense in Asperger's syndrome. Israel J Psychiatry Relat Sci 1998;35:293299. GILLBERG C, COLEMAN M. The biology of the autistic syndromes. Clinics in Developmental Medicine no. 126, 2nd rev. edn. London, New York: MacKeith Press, 1992. FARAONE SV, BIEDERMAN J, WEIFFENBACH B et al. Dopamine D4 gene 7-repeat allele and attention decit hyperactivity disorder. Am J Psychiatry 1999;156:768770. WALDMAN ID, ROWE DC, ABRAMOWITZ A et al. Association and linkage of the dopamine transporter gene and attentiondecit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet 1998;63:17671776. SMALLEY SL, BAILEY JN, PALMER CG et al. Evidence that the dopamine D4 receptor is a susceptibility gene in attention decit hyperactivity disorder. (Published erratum appears in Mol Psychiatry 1999;4:100.) Mol Psychiatry 1998;3:427 430. ROWE DC, STEVER C, GIEDINGHAGEN LN et al. Dopamine DRD4 receptor polymorphism and attention decit hyperactivity disorder. Mol Psychiatry 1998;3:419426. LECKMAN JF, COHEN DJ. Recent advances in Gilles de la Tourette syndrome: implications for clinical practice and future research. Psychiatr Dev 1983;1:301316. COMINGS DE, WU S, CHIU C et al. Polygenic inheritance of Tourette syndrome, stuttering, attention decit hyperactivity, conduct, and oppositional deant disorder: the additive and subtractive effect of the three dopaminergic genes DRD2, D beta H, and DAT1. Am J Med Genet 1996;67: 264288.

50. 51.

73.

74. 75.

52.

53. 54. 55. 56. 57.

76. 77. 78.

79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89.

58. 59. 60. 61. 62. 63. 64. 65. 66. 67.

90.

68.

91. 92. 93.

69. 70. 71. 72.

330