Autism and the pervasive developmental disorders
- Development of diagnostic concepts
- Childhood autism
- Clinical features
- Epidemiology and demographics
- Course and prognosis
- Rett's syndrome
- Clinical features
- Epidemiology and demographics
- Course and prognosis
- Childhood disintegrative disorder
- Clinical features
- Epidemiology and demographics
- Course and prognosis
- Asperger's syndrome
- Clinical features
- Epidemiology and demographics
- Course and prognosis
- Atypical autism/PDD not otherwise specified
- Differential diagnosis
- Educational approaches
- Behavioural interventions
The pervasive developmental disorders (PDDs) are characterized by patterns of deviance and delay in social-communicative development in the first years of life, which are associated with restricted patterns of interest or behaviour.
The prototypic PDD is childhood autism; other conditions included in the PDD class in ICD-10 (1) include Rett's syndrome, childhood disintegrative disorder, Asperger's syndrome, and atypical autism.
Except for one additional category in ICD-10 (hyperkinetic stereotyped movement disorder) the disorders included in ICD-10 and DSM-IV (2) are essentially identical. In this article each of these conditions will be reviewed in terms of its clinical features, definition, epidemiology, course, and aetiology; final sections of the article address aspects of treatment and prevention for the group of disorders as a whole.
Development of diagnostic concepts
Autism was first recognized by Leo Kanner (3) in his classic report of 11 children with ‘autistic disturbances of affective contact'. Kanner noted that these children appeared to be unable to relate—apparently from the beginning of life; they also exhibited atypical language, unusual responses to the environment, and difficulties in dealing with change. He used Bleuler's earlier term ‘autistic' to convey the children's social isolation. Although children with autism had undoubtedly previously been observed, (4) it was Kanner's particular genius to so precisely describe the condition. At the same time certain of his initial impressions were incorrect, for example his use of the term autism introduced an (originally) unintended confusion with schizophrenia and assumed that the children had normal intellectual potential. Subsequently, it became clear that autism and schizophrenia were distinct and that attribution of low IQ scores to ‘poor testability' were incorrect. (5) While non-verbal cognitive abilities may (relatively) be preserved (6) most children with autism, perhaps as many as 70 per cent, have full-scale IQ scores in the mentally retarded range. (7) Although suggesting that the condition was congenital, Kanner also mentioned that parents were very well educated and successful; this led to a notion, common during the 1950s, that autism might somehow result from deviant patterns of care. A large body of evidence shows that this is most certainly not the case. (8) It is clear that families of children with autism come from all social classes and circumstances. (9)
Both before and after Kanner's work other clinicians had attempted to describe syndromes with at least some phenomenological similarity to autism. For example, shortly after the turn of the century a special educator working in Vienna, Theodor Heller, (10) reported children who had a period of several years of normal development prior to a marked regression with loss of skills in multiple areas and minimal recovery. He initially termed the condition dementia infantilis; subsequently it has been referred to as Heller's syndrome, disintegrative psychosis, or childhood disintegrative disorder. (11) Once it develops the condition is indistinguishable from autism,(12) but it is accorded separate diagnostic status since it appears distinctive in terms of onset and course.
In the year following Kanner's description, a medical student, Hans Asperger, (13) described four boys with marked social problems, unusual perseverative interests, and motor clumsiness. Although unaware of Kanner's work, Asperger used the term ‘autistic psychopathy' to describe this condition. Unknown to the English-speaking world for many years, his description had points of difference, as well as similarity, to Kanner's report. For example, verbal abilities tended to be an area of strength, concerns typically did not arise until later in the preschool period, and there was a tendency for the condition to run in families—particularly in fathers. Lorna Wing's (14) report of Asperger's work and publication of a series of cases brought wider attention to the diagnostic concept. The validity of this condition, particularly apart from higher functioning autism, remains the topic of much debate. A major complication has been the marked differences in the ways in which the concept has been used and its potential overlap with other diagnostic concepts (e.g. schizoid personality, (15) semantic–pragmatic disorder, (16) and right hemisphere learning problems (17)). As a result, the literature on this condition is difficult to interpret, although several areas of potential differences from autism have been identified (e.g. neuropsychological profiles (18) and family history (19)).
In 1966, Andreas Rett described an unusual syndrome in girls that was characterized by a history of initial normal development, subsequent head growth deceleration, and the development of characteristic clinical findings such as breathing difficulties, movement problems, in addition some features suggestive of autism were present. (20) His findings were replicated and extended by Hagberg et al. (21) As more extensive information became available it was clear that the more ‘autistic-like' phase of the syndrome was relative brief, but this is a major rationale for its inclusion in the PDD class. (22)
Recent editions of both ICD and DSM have included a ‘subthreshold' category (termed either atypical autism or pervasive developmental disorder or unspecified pervasive developmental disorder). In some ways this notion has historical links to earlier diagnostic concepts. (23) Research here has been less advanced than that for other disorders—no doubt reflecting the problems intrinsic to ‘subthreshold' disorders. Several attempts have recently been made to identify potential subgroups within the rather heterogeneous disorder, but none has yet achieved general acceptance.
Social deficits of a particular type remain a hallmark of autism. The nature of this deficit varies, somewhat, over time but remains a source of great disability to the affected individual throughout life. (24) In younger and more impaired individuals there may be little interest in social interaction; less impaired individuals may come to a passive acceptance of social interaction. Social interest may be more marked among those functioning at a higher level, but it is often eccentric and one-sided. (25) Manifestations of the social dysfunction include difficulties in the use of eye contact or other non-verbal social cues, in social emotional reciprocity and empathy, in activities involving shared interests with others, and with peer relationships (see Table 1). As Rutter (26) suggested these problems do not simply reflect mental retardation. Abnormalities in communication (not only in language) are also observed. In a substantial minority (perhaps 40 per cent) of cases the child never acquires the capacity for communicative speech; among individuals who do talk various unusual features of language are observed such as echolalia, idiosyncratic language, deficits in prosody, and pronoun reversal. (27) Deficits in pragmatic language are particularly striking. As with the social disturbance the deficits observed are not solely due to mental retardation. Various unusual behaviours are subsumed under the term ‘resistance to change'. These behaviours include literal resistance to change (insistence on sameness), stereotyped and repetitive motor mannerisms, strict adherence to non-functional routines, interest in non-functional parts of objects. Various other features may be observed, for example unusual sensitivities to environment, attachments to unusual objects, and so forth.
ICD-10 Criteria for Childhood Autism
A. Abnormal or impaired development is evident before the age of 3 years in at least one of the following areas:
- receptive or expressive language as used in social communication;
- the development of selective social attachments or of reciprocal social interaction;
- functional or symbolic play.
B. A total of at least six symptoms from (1), (2) and (3) must be present, with at least two from (1) and at least one from each of (2) and (3)
1. Qualitative impairment in social interaction are manifest in at least two of the following areas:
- a. failure adequately to use eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction;
- b. failure to develop (in a manner appropriate to mental age, and despite ample opportunities) peer relationships that involve a mutual sharing of interests, activities and emotions;
- c. lack of socio-emotional reciprocity as shown by an impaired or deviant response to other people’s emotions; or lack of modulation of behavior according to social context; or a weak integration of social, emotional, and communicative behaviors;
- d. lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g. a lack of showing, bringing, or pointing out to other people objects of interest to the individual).
2. Qualitative abnormalities in communication as manifest in at least one of the following areas:
- a. delay in or total lack of, development of spoken language that is not accompanied by an attempt to compensate through the use of gestures or mime as an alternative mode of communication (often preceded by a lack of communicative babbling);
- b. relative failure to initiate or sustain conversational interchange (at whatever level of language skill is present), in which there is reciprocal responsiveness to the communications of the other person;
- c. stereotyped and repetitive use of language or idiosyncratic use of words or phrases;
- d. lack of varied spontaneous make-believe play or (when young) social imitative play
3. Restricted, repetitive, and stereotyped patterns of behavior, interests, and activities are manifested in at least one of the following:
- a. An encompassing preoccupation with one or more stereotyped and restricted patterns of interest that are abnormal in content or focus; or one or more interests that are abnormal in their intensity and circumscribed nature though not in their content or focus;
- b. Apparently compulsive adherence to specific, nonfunctional routines or rituals;
- c. Stereotyped and repetitive motor mannerisms that involve either hand or finger flapping or twisting or complex whole body movements;
- d. Preoccupations with part-objects of non-functional elements of play materials (such as their oder, the feel of their surface, or the noise or vibration they generate).
C. The clinical picture is not attributable to the other varieties of pervasive developmental disorders; specific development disorder of receptive language (F80.2) with secondary socio-emotional problems, reactive attachment disorder (F94.1) or disinhibited attachment disorder (F94.2); mental retardation (F70-F72) with some associated emotional or behavioral disorders; schizophrenia (F20.-) of unusually early onset; and Rett’s Syndrome (F84.12).
World Health Organization. (1992). International classification of diseases: Diagnostic criteria for research (10th edition). Geneva, Switzerland: Author.
Above: Table 1 ICD-10 criteria for childhood autism (F84.0)
For over 20 years following Kanner's original report there was much disagreement about autism. Gradually evidence began to accumulate that suggested the role of central nervous system dysfunction in pathogenesis—for example, children with autism were prone to develop seizures of various types, exhibited delayed development of hand dominance, and showed persistent primitive reflexes. Differences in clinical features, course, and family history supported the distinctiveness of autism (for instance, apart from schizophrenia). (28,29)
By 1978 there was a substantial body of work on the validity of autism. Rutter synthesized this in his influential definition of autism, (28) which required the presence of patterns of delay and deviance in the areas of social and communication development that were not simply the result of developmental delay along with the group of unusual behaviours subsumed under the term ‘insistence on sameness'. Onset before 30 months of age was required.
In the ninth revision of ICD (1977) infantile autism was included within the category ‘Psychoses with onset in childhood'—continuing to perpetuate the notion that the condition might be related to schizophrenia. A somewhat different approach was taken in DSM-III, (30) which was much influenced by the work of Rutter and where autism was placed in a new class of disorder—the pervasive developmental disorders. The latter term has been the topic of some debate, although a better term has yet to be proposed and, in any case, the term PDD has now come into general usage in both DSM and ICD. (31,32)
The name chosen in DSM-III (‘Infantile autism') was consistent with Kanner's original report but reflected a lack of developmental orientation; these concerns were addressed in DSM-IIIR. (33) A detailed, and more developmentally oriented, set of criteria were provided and the polythetic approach adopted (i.e. minimal numbers of criteria had to be exhibited in different areas). In contrast to Rutter (29) and DSM-III, (30) an early age of onset was not required. Unfortunately, the greater concern with developmental issues also resulted in an overinclusive diagnostic concept and it became apparent that additional work would be needed. Further impetus was given to this effort by pending changes in ICD-10. (1)
Various data were collected for both ICD-10 and DSM-IV. In addition to literature reviews and commissioned data reanalyses, an international effort was undertaken to derive criteria for autism. (34) These data suggested the following.
- DSM-IIIR tended to overdiagnose autism.
- There was convergence between the diagnoses of experienced clinicians and the draft ICD-10.
- There was some basis for change in the latter system (relative to number and wording of diagnostic criteria).
- There was support for inclusion of other conditions (for instance, Rett's syndrome, Asperger's syndrome, and childhood disintegrative disorder) within the PDD class.
As a result there was general agreement between the two official diagnostic systems in terms of the approach to diagnosis of autism and related conditions.
Autism is defined (see Table 1) on the basis of characteristic problems in three areas: social interaction, communication and play, and restricted patterns of interest. By definition, autism must be present by the age of years. ICD-10 provides for various ways in which a diagnosis of atypical autism can be made—for example, because of failure to meet age or onset or behavioural criteria. Data on this system suggest that it has good agreement with the diagnoses of experienced clinicians, avoids the problem of the overdiagnosis of autism in the most mentally handicapped persons, and has reasonably good reliability.
Epidemiology and demographics
Over 20 epidemiological studies of autism have been conducted, with reported prevalence rates ranging from 0.7 per 10 000 to 21.1 per 10 000 with a median value of prevalence estimate of 4 to 5 per 10 000. (35) Several recent studies have reported somewhat higher rates of the condition, in the order of 1 per 1000; it remains unclear whether the condition has actually increased or whether the apparent increase relates to broader definitions of autism or other factors.
Epidemiological studies have clarified that there is no association of autism with upper socioeconomic status. Early impressions of such associations were the result of referral bias. A number of studies, including both epidemiological and clinically referred samples, report higher rates of autism in boys than in girls (typically 3.5:1 or 4:1). This ratio varies with IQ level, i.e. females with autism who have IQs in the normal range are probably 50 times less common than males. (36) The explanation for this sex difference remains unclear. It is possible that the degree of insult required to produce autism in females must be greater than for males.
Course and prognosis
Childhood autism is a chronic disability; about two-thirds of individuals continue to require significant supervision and support as adults. The remaining one-third are capable of some degree of personal independence and self-sufficiency, with perhaps 1 in 10 have a reasonably good outcome and able to live independently. (37) However, even in the highest functioning individuals marked social problems persist. There is some suggestion that outcome has improved over the past decade as a result of earlier diagnosis and more intensive intervention. (38)
Changes in the degree of social relatedness, communication, and self-help skills are observed with increases in developmental level. A major medical complication is seizure disorder, which is observed in up to 25 per cent of individuals. Seizures may have their onset at any point, but adolescence and early childhood are particularly common times.(39,40) Factors that predict long-term outcome include the presence of some communicative speech by the age of 5 or 6, and the non-verbal intellectual level.
Early interest centred on the possibility that experiential factors might somehow cause autism, but a host of research findings suggests that this is not the case. Rather, a fundamental disturbance in the central nervous system is implicated. At the same time important aspects of psychological development in autism have been investigated.
Disabilities affecting attentional mechanisms, arousal, sensory deficits, memory management, and complex information processing, among others, have been proposed as primary deficits underlying the social impairment in autism. Although each of these helps us understand some aspects of the condition, none has, as yet, provided a more comprehensive account of the condition as a whole. (41)
Among the most influential recent theories attempting to do that is the hypothesis that posits a lack of a central drive for coherence in children with autism, with the consequent focus on dissociated fragments of their environment rather than integrated ‘wholes', leading to a fragmentary and overly concrete experience of the world. (42) Another cognitive account of autism posits that the commonly found difficulties in abstracting rules, inhibiting irrelevant responses, shifting attention, and profiting from feedback as well as in maintaining ‘on-line' different pieces of information while a decision is made—the so-called ‘executive functions'—underlie the social, communicative, and behavioural disabilities in autism. (43) Although both these theories—‘weak central coherence' and ‘executive dysfunction'—provide insightful new views of well-known clinical phenomena, neither phenomena can be seen as specific to autism (that is, relative to other developmental disorders) as the pervasive social impairment.
Probably the most influential current cognitive hypothesis focuses on mechanisms directly impacting on social understanding. This view, called the ‘theory of mind' hypothesis, posits that autism is caused by the child's inability to attribute mental states such as beliefs and intentions to others. Devoid of this ability, individuals with autism are thought to be unable to infer the thoughts and motivations of others, thus failing to predict their behaviour and adjust their own actions accordingly, which results in a lack of reciprocity in communication and social contact. (44) Although more than 30 studies have documented such deficits in autism, there are still many limitations to this hypothesis. For example, more able individuals with autism can provide detailed accounts of other people's intentions, beliefs, and feelings—i.e. they exhibit ‘theory of mind' skills—and yet may be totally unable to utilize these capacity in their spontaneous social adjustment. Such phenomena suggest that factors other than a cognitive understanding of mental phenomena are required for a person to meet the demands of everyday social life.
Researchers are now proposing more integrative theories capturing the synergistic nature of social–affective, motivational, and cognitive mechanisms facilitating socialization. (45) Of great interest in the past few years has been the confluence of experimental psychological paradigms and functional neuroimaging studies focusing on the same constructs. This new trend is leading to new insights into brain systems subserving basic social mechanisms such as gaze behaviour, social-affective responses, and thinking about other people's intentions and beliefs, (46) all of which are greatly compromised in autism.
The importance of biological factors in the pathogenesis of autism is suggested by its association with mental retardation and seizure disorder, other medical conditions, and the role of genetic factors. (8,47) Individuals with autism are at increased risk for developing seizures throughout childhood and adolescence. (47,48) Various non-specific neurological signs and symptoms may also be observed.
Autism has been associated with a host of medical conditions; but the absence of population data and rigorous diagnostic assessment makes such associations difficult to interpret. For example, early reports suggested an association with congenital rubella, but this now seems questionable given the diagnostic dilemmas and the observation that ‘autistic-like' features diminish over time. (49) Gillberg (50) argues that medical conditions may be associated with autism in as many as one-third of cases, but Rutter et al. (51) suggest that a more reasonable figure would be roughly 10 per cent of all cases. The strongest associations are with fragile X syndrome and tuberous sclerosis—both conditions having a strong genetic component.
Fragile X syndrome is an X-linked mental retardation syndrome involving a mutation characterized by a triplet repeat of cytosine– guanine–guanine (CGG) that may amplify with succeeding generations. It is associated with a characteristic facial appearance, enlarged testicles, mental retardation, and some autistic features. Early reports suggesting high rates of fragile X in autism have now been modified; fragile X affects perhaps 1 per cent of all individuals with autism. (52)
The autosomal dominant disorder tuberous sclerosis is characterized by abnormal tissue growth, or benign tumours (hamartomas), in the brain and in other organs. The condition, which may affect 1 in 10 000 individuals, is variably expressed; the phenotype ranges from minor skin problems or seizures to severe mental retardation with intractable seizures. The rate of this condition in autism (0.4–2.8 per cent) is significantly increased. (53)
The early impression that the role of genetic factors was limited has been modified given the association of autism with conditions like fragile X and tuberous sclerosis, and the results of twin and other family studies. Studies of monozygotic and dizygotic twins revealed higher levels of concordance for monozygotic twin pairs and elevations (relative to population rates) of autism in dizygotic twins as well. (8) General studies suggest that the recurrence risk of autism in siblings is in the order of 2 to 3 per cent—a 50- to 100-fold increase over the population rates. There also appear to be high rates of other developmental problems in siblings, raising the possibility that what is inherited may be a more general predisposition to developmental difficulties. Recent work also suggests elevated rates of anxiety and mood disorders in family members. However, specific modes of inheritance remain unclear. It now appears that several interacting genes are probably involved in the pathogenesis of autism. Efforts are underway to identify candidate genes and it is likely that some genetic forms of autism will be identified over the next few years. Although several studies have shown noted increased rates of pre-, peri-, and neonatal complications in children with autism, it is possible that some of these difficulties may reflect a genetic vulnerability in the child or that there may be an interaction of genetic and perinatal factors. (8)
Attempts have been made to identify neuropathological and neuroanatomical correlates of autism. Areas of interest have included the cortical areas responsible for language and social interaction (frontal and temporal lobes) as well as the neostriatum and cerebellum. (47) Interest in the cerebellums followed the report of reduced cerebellar size in the neocerebellar vermal lobules VI and VII; this observation has not proven readily replicable. Some individuals with autism have enlarged brains and head sizes, whereas others, particularly the more retarded, have smaller head sizes. (54) Neuropathological studies have suggested possible cellular changes in areas of the brain such as the hippocampus and amygdala.
Various neurotransmitter systems have been studied. Probably the most robust finding has been the observation that about one-third of children with autism have increased peripheral levels of serotonin. This finding is not specific to autism and its significance remains unclear. (55) Studies of other neurotransmitters such as dopamine produced inconsistent findings. The possible involvement of dopamine is suggested by the high levels of stereotyped behaviours in autism—behaviours which can be induced in animals by the administration of agents (stimulants) that affect levels of dopamine in the brain. Agents such as the neuroleptics, which block dopamine receptors, are effective in reducing the stereotyped and hyperactive behaviours of many autistic children. Another hypothesis has centred on the possible role of endogenous opioids, in that overproduction of such compounds might lead to social withdrawal and unusual sensitivities and behaviours. This has led to the administration of opioid antagonists such as naltrexone in autism; unfortunately results have been disappointing. Studies of the immune system in autism have been relatively uncommon and findings inconsistent.
Early pre- and perinatal histories are generally unremarkable in Rett's syndrome, as is very early development. Usually within the first year or two of life development begins to slow or actually regress and various motor problems—typically including unusual and characteristic hand-washing stereotypies start to develop. (56) A significant loss of developmental skills occurs and head growth decelerates. (21) The potential for misdiagnosis of autism is greatest during this time. During school age developmental regression often stabilizes and children are more socially responsive. As individuals with Rett's syndrome approach adolescence they are frequently subject to increased spasticity, scoliosis, loss of ambulation, bruxism, hyperventilation, areophagia, apnoea, and seizures. (57) Although debated, (58) the inclusion of Rett's syndrome in the PDD class reflects an awareness of the confusion with autism and the importance of including the condition somewhere. (59)
Various diagnostic criteria for Rett's syndrome have been developed. (60) As presently defined in ICD-10 (see Table 2) the condition develops after some months of normal development; head circumference is normal at birth but begins to decelerate between 5 and 48 months. Characteristic midline hand-wringing or hand-washing stereotypies develop and purposeful hand movements are lost.
ICD-10 Diagnostic criteria for Rett's syndrome (F84.2)
In most cases onset is between 7 and 24 months of age. The most characteristic feature is a loss of purposive hand movements and acquired fine motor manipulative skills. This is accompanied by loss, partial loss or lack of development of language; distinctive stereotyped tortuous wringing or "hand-washing" movements, with the arms flexed in front of the chest or chin; stereotypic wetting of the hands with saliva; lack of proper chewing of food; often episodes of hyperventilation; almost always a failure to gain bowel and bladder control; often excessive drooling and protrusion of the tongue; and a loss of social engagement. Typically, the children retain a kind of "social smile", looking at or "through" people, but not interacting socially with them in early childhood (although social interaction often develops later). The stance and gait tend to become broad-based, the muscles are hypotonic, trunk movements usually become poorly coordinated, and scoliosis or kyphoscoliosis usually develops. Spinal atrophies, with severe motor disability, develop in adolescence or adulthood in about half the cases. Later, rigid spasticity may become manifest, and is usually more pronounced in the lower than in the upper limbs. Epileptic fits, usually involving some type of minor attack, and with an onset generally before the age of 8 years, occur in the majority of cases. In contrast to autism, both deliberate self-injury and complex stereotyped preoccupations or routines are rare.
Above: Table 2 ICD-10 criteria for Rett's syndrome (F84.2)
Epidemiology and demographics
Prevalence estimates range from 1 per 12 000 to 1 per 23 000 females; cases are observed in all racial and ethnic groups. (61,62) Rett's syndrome may account for one-quarter to one-third of progressive developmental disabilities among females. (61)
To date, Rett's syndrome has been unequivocally described only in females. While male sex is not exclusionary diagnostic and case reports of males with some features of Rett's syndrome have been appeared, no male who exhibits strict diagnostic criteria has yet been identified. (56)
Course and prognosis
Various clinical stages of the condition have been identified. (56) Early developmental losses may be difficult to detect initially but become more marked with time. Purposeful hand movements are often then lost, as are speech skills. Ataxia and gait abnormalities are noted in those patients who had acquired the ability to walk, unusual breathing patterns (hyperventilation and/or apnoea) and seizures may also be observed. Social and communication skills may improve in middle childhood, although motor problems are more pronounced. During the final phase (roughly after age 10) progressive scoliosis and spasticity are observed, while cognitive function stabilizes and seizure activity may diminish. There is a dearth of information on adults with the condition. There does appear to be an increased risk of sudden death due to seizures and/or respiratory difficulties. (63)
Rett (20) originally speculated that the condition might be associated with high peripheral ammonia levels, but this was incorrect. While no specific biological marker for the condition has been identified, several lines of report support a neurobiological basis for the condition (e.g. cortical atrophy on brain scan, decreased brain weight and loss of neurones, and changes in the substantia nigra and caudate nucleus on autopsy). (56) Results of neurochemical studies have been contradictory. Genetic data are limited. The meaning of the observed gender difference remains unclear, but it is possible that a dominant X-linked new mutation might cause males to be aborted. (64)
Childhood disintegrative disorder
In this condition an ‘autistic-like' clinical pictures develops after a prolonged period of normal development. (10) More than 100 cases have now been reported; the condition is rare but probably underdiagnosed. (11) Essential clinical features include a relatively long period of normal development followed by a marked developmental regression and development of various ‘autistic-like' features; onset is typically between the ages of 3 and 4 years.
Onset can be relatively abrupt (days to weeks) or more gradual (weeks to months); a premonitory phase of non-specific anxiety or agitation may be observed. Parents often note associations between the onset of the condition and various psychosocial or medical events. (65,66 and 67) Such associations are probably correlational rather than causative, in that they are frequently observed at around this age. Factors reported include birth of a sibling or death of a grandparent, admission to hospital for elective surgery, and immunizations. (68)
Once the condition is established it resembles autism, i.e. social and communicative skills are markedly impaired and various unusual behaviours and restricted interests are typically observed. (69) Given the behavioural similarity to autism, it might be argued either that the condition does not warrant separate diagnostic recognition or that the condition is inevitably the result of an association with some progressive medical condition. However, the pattern of onset is quite distinctive, the outcome appears to be even worse than in autism, and usually even with very intensive medical evaluations no general medical condition accounting for the regression is identified.
Criteria for the disorder are listed in Table 3. By definition the disorder cannot coexist with autism or another other explicitly defined pervasive developmental disorder, schizophrenia, elective mutism, or the syndrome of acquired aphasia with epilepsy.
ICD-10 diagnostic criteria for other childhood disintegrative disorder (F84.3)
Diagnosis is based on an apparently normal development up to the age of at least 2 years, followed by a definite loss of previously acquired skills; this is accompanied by qualitatively abnormal social functioning. It is usual for there to be a profound regression in, or loss of, language, a regression in the level of play, social skills, and adaptive behaviour, and often a loss of bowel or bladder control, sometimes with a deteriorating motor control. Typically, this is accompanied by a general loss of interest in the environment, by stereotyped, repetitive motor mannerisms, and by an autistic-like impairment of social interaction and communication. In some respects, the syndrome resembles dementia in adult life, but it differs in three key respects: there is usually no evidence of any identifiable organic disease or damage (although organic brain dysfunction of some type is usually inferred); the loss of skills may be followed by a degree of recovery; and the impairment in socialization and communication has deviant qualities typical of autism rather than of intellectual decline. For all these reasons the syndrome is included here rather than under F00-F09. Includes: dementia infantilis disintegrative psychosis Heller's syndrome symbiotic psychosis Excludes: acquired aphasia with epilepsy (F80.3) elective mutism (F94.0) Rett's syndrome (F84.2) schizophrenia (F20.-)
Above: Table 3 ICD-10 criteria for other childhood disintegrative disorder (F84.3)
Epidemiology and demographics
Epidemiological data are quite limited. (11) The limited data available would suggest that the disorder is at least 10 per cent as common as autism; (69) Burd et al. (70) suggested a comparable prevalence rate of 1 in 100 000.
Initial cases seemed to be equally distributed between males and females, but it now seems likely that cases of Rett's syndrome may have been included in early case series. Recent reviews have noted a preponderance of males. (11)
Course and prognosis
In about 75 per cent of cases the deterioration reaches a plateau, in that there is no further loss of skills, but subsequent gains tend to be minimal. Thus the child who previously was normally socially related, speaking in full sentences, and toilet-trained becomes indifferent to social interaction, loses all expressive language and toilet skills, and remains mute and relatively low functioning. (12) In the remainder of cases there is more limited recovery, for example the child regains the capacity to speak but only in single words or only echoes language. Particularly if a progressive metabolic or neuropathological process is present, the developmental progression may continue until death ensues; such cases often have a later onset. (71) Life expectancy otherwise appears to be normal. In a very small number of cases significant recovery has been noted.
Various lines of evidence suggest the importance of neurobiological factors in pathogenesis. Occasionally medical conditions such as the neurolipidoses, metachromatic leukodystrophy, Addison–Schilder's disease, and subacute sclerosing panencephalitis are associated with the condition. Rates of electroencephalograph abnormalities and seizure disorders are of roughly the same frequency as seen in autism.
This condition is characterized by impairments in social interaction and restricted interests and behaviours as seen in autism. However, the child's early development is marked by a lack of any clinically significant delay in spoken or receptive language, cognitive development, self-help skills, and curiosity about the environment. Consistent with Asperger's (13) original report all-absorbing and intense circumscribed interests as well motor clumsiness are typical, but are not required for diagnosis. The validity of this condition, apart from high-functioning autism and PDD not otherwise specified ( PDD-NOS) is controversial. Available research is difficult to interpret given the markedly different ways in which the diagnostic concept has been used. Differences are more likely to be noted relative to autism if a rather stringent diagnostic approach is used. Evidence for external validity of the condition relative to autism includes differences in neuropsychological profiles, patterns of comorbidity, and family history.
Persons with Asperger's syndrome often exhibit a somewhat eccentric social style rather than the more passive or aloof style noted in autism; for example, they may engage others in very one-sided conversations about their area of special interest. They over-rely on rigid rules for social interaction and may fail to ‘see the forest for the trees' in social matters (e.g. an appreciation of exactly when the usual rules do not apply is as important as when they do).
While early speech-communication skills are apparently normal, certain aspects of communication become more deviant over time. Prosody may be poor, rate of speech may also be unusual, or it may have a somewhat disorganized, tangential, and circumstantial quality. The issue of whether such persons are at increased risk for thought disorder and psychosis remains unresolved, but some part of this impression probably reflects these difficulties.
It is rather typical for patients to amass considerable factual information about their topic of interest, which they pursue with great intensity; Asperger originally observed that family life may revolve around the topic of special interest. He also suggested that motor clumsiness was present and, although not required for the diagnosis, there is often a history of motor delay and persistent motor awkwardness—for instance, the child may talk before he walks, have trouble catching a ball, learning to ride a bicycle, and so forth.
Differences in neuropsychological profiles have been reported. (72) A stringent diagnostic approach may suggest areas of relative strengths (auditory and verbal skills and rote-learning) and weakness (visuomotor and visuoperceptual skills); this pattern differs from that observed in higher functioning individuals with autism. (6) Interest in the condition has revolved around the possibility that it might represent a transition between autism and other disorders such as schizophrenia. Associated conditions have included depression, anxiety and other mood problems, violence, and other psychotic conditions. (72) Unfortunately, almost all of this literature rests on case reports; controlled studies are needed.
The ICD-10 criteria for Asperger's syndrome are given in Table 4. As presently defined the social deficit is the same as that in autism. In contrast to autism, however, early language, cognitive, and other skills are normal early in life. By definition, the case does not meet the criteria for childhood autism. Miller and Ozonoff (73) note that several aspects of the current definition can be problematic; Asperger consistently felt that the syndrome he described differed from Kanner's autism. (74) Thus the current definition almost certainly will be refined (or discarded) in future editions of ICD and DSM.
ICD-10 Diagnostic Criteria for Research : F84.5 - Asperger’s Syndrome
A. A lack of any clinically significant general delay in spoken or receptive language or cognitive development. Diagnosis requires that single words should have developed by two years of age or earlier and that communicative phrases be used by three years of age or earlier. Self-help skills, adaptive behaviour and curiosity about the environment during the first three years should be at a level consistent with intellectual development. However, motor milestones may be somewhat delayed and motor clumsiness is usual (although not a necessary diagnostic feature). Isolated special skills, often related to abnormal preoccupations, are common, but are not required for diagnosis.
B.Qualitative abnormalities in reciprocal social interaction (criteria as for autism).
C.An unusually intense circumscribed interest or restrictive, repetitive, and stereotyped patterns of behaviour, interests and activities (criteria as for autism; however, it would be less usual for these to include either motor mannerisms or preoccupations with part-objects or non-functional elements of play materials).
D.The disorder is not attributable to other varieties of pervasive developmental disorder; schizotypal disorder (F21); simple schizophrenia (F20.6); reactive and disinhibited attachment disorder of childhood (F94.1 and .2); obsessional personality disorder (F60.5); obsessive-compulsive disorder (F42).
Above: Table 4 ICD-10 criteria for Asperger's syndrome (F84.5)
Epidemiology and demographics
Estimates of the prevalence vary markedly depending on the stringency of the definition used. A stringent approach to diagnosis would suggest a rate in the order of 1 in 10 000, but a much less stringent approach may yield one in several hundred. (72) Asperger (13) originally reported the condition only in boys, although Wing (14) reported on girls with the condition. There does appear to be a male predominance in the order of 9 to 1; similar sex ratios are observed in autism not associated with mental retardation.
Course and prognosis
Given the recency of official and consensual definitions there are few systematic follow-up studies. Asperger's original (13) impression was of a favourable long-term prognosis. Although he tempered this view somewhat over time, he continued to insist that the condition had a better outcome than autism. (74) Many individuals can attend regular school with some additional support; unfortunately such children may be seen as eccentric and are often prime targets for being victimized. Better verbal skills can mislead educators about the child's vulnerability in other areas, and difficulties academically may be misattributed to wilful non-compliance. There is the impression that these individuals are capable of greater degrees of personal and occupational self-sufficiency than those with autism, but definitive data are lacking. It does appear that the social difficulties persist into adulthood.
Although the cause of Asperger's syndrome remains unknown, the report of high rates of the condition in family members and the reports of occasional familial associations with autism suggests the potential importance of genetic factors. Neurobiological information on the condition is limited. The potential association of the condition with specific neuropsychological profiles is of some interest.
Atypical autism/PDD not otherwise specified
Atypical autism in ICD-10, and the term ‘Pervasive developmental disorder not otherwise specified' ( PDD-NOS) in DSM-IV, refers to what is a residual diagnostic category. ICD-10 provides the possibility for various forms of special coding—for example, failure to meet the onset criteria for autism, failure to meet developmental/behavioural criteria, failure to meet both, and so forth. Essentially this diagnostic concept refers to a ‘subthreshold' condition that has similarities to autism and the other explicitly defined PDDs but which does not meet criteria.
Various attempts have been made to identify specific subgroups within this broader category. (75) It is often the case that social and/or communicative skills are relatively preserved but the child exhibits unusual sensitivities or affective responses. It is likely that the term presently encompasses a number of conditions which may be identified in the future.
Autism and related PDDs must be differentiated from each other, from the specific developmental disorders (e.g. of language), from mental retardation not associated with PDD, and from other conditions. In childhood autism the apparent onset of the disorder is almost always within the first years of life. In addition, the child must exhibit the characteristic problems in social interaction, communication, and restricted interests or behaviours. Difficulties in diagnosis can be seen in very young children who do not yet exhibit all features of the disorder. (76) Occasionally parents of children with autism will report relatively normal development up to 18 to 24 months of age, a careful history will often reveal some pre-existing abnormality. Early development is unequivocally normal prior to the marked developmental regression seen in childhood disintegrative disorder. In Rett's syndrome, head growth deceleration, marked mental retardation, characteristic hand-washing stereotypies, and other features are observed. In Asperger's syndrome, early cognitive and language development is apparently normal; the child's difficulties often become more apparent as he or she is exposed to peers. Some features suggestive of autism are present in PDD-NOS/atypical autism, but the child does not meet the full criteria for autism or another of the PDDs.
In mental retardation not associated with PDD, social and communicative skills are typically on a par with the child's overall intellectual ability. Diagnostic differentiation can be most difficult in persons with severe and profound mental retardation where assessment is more difficult and stereotyped movements common. Occasionally language and other specific developmental disorders may be confused with autism/PDD. Usually, however, the child's social abilities are preserved and the child is very commmunicative non-verbally. Schizophrenia rarely has its onset in childhood and almost never before the age of 5 years; characteristic symptoms in children may be of a somewhat less sophisticated form than in adulthood.
On occasion, selective mutism or social anxiety disorder may be confused with a PDD (particularly PDD-NOS/atypical autism). However, in selective mutism the child can speak in some situations. Similarly, children with anxiety in social situations will usually not exhibit the other symptoms characteristic of autism/PDD. The unusual behaviour and interests of children with obsessive–compulsive disorder may be taken to suggest autism or PDD, but social and language-communication skills are preserved.
Schizophrenia rarely has its onset in childhood, particularly before the age of 10. The typical pattern of onset is one of relatively acute deterioration with delusions, hallucinations, and other features typical of schizophrenia. (28,29) Occasionally, schizophrenia in children has a more insidious onset and is preceded by a range of non-specific developmental and behavioural problems, but even in such cases characteristic features of schizophrenia are exhibited.
In considering the differential diagnosis of conditions that present with regression it is important to review carefully previous diagnostic evaluations. Occasionally progressive neuropathological condition may have its onset in childhood. In the Landau–Kleffner syndrome (acquired aphasia with epilepsy) social skills should be relatively preserved even in the face of an extensive aphasia.
Sometimes children who have experienced marked neglect may present with social difficulties, initially suggesting autism or PDD. However, in reactive attachment disorder the history of severe neglect is observed and, as the name of the condition implies, social deficits should remit substantially if an appropriate environment is provided.
Goals for treatment include promoting learning and reducing behaviours that interfere with learning. Treatment is best based on a comprehensive view of the child and his or her strengths and areas of need. A structured and individualized intervention programme is needed. Various professionals such as speech pathologists, special educators, occupational and physical therapists, and so forth may be involved. (77,78) Goals for intervention will vary depending on developmental level, life circumstance, and clinical context—for example, vocational factors will be more important during adolescence, and for individuals with conditions like Rett's syndrome the efforts of other professionals (orthopaedists and respiratory therapists) may be needed.
Children with autism and other PDDs generally require an intensive and highly structured intervention programme. More able children may be able to tolerate regular classroom situations, with appropriate support, but more impaired children often need higher levels of teacher supervision and a more intensive classroom setting. (77) For lower-functioning children areas of priority include the ability to tolerate adult guidance and intrusion, to follow routines, to develop communicative abilities, and move from associational to more conceptual learning modalities. (78) The classroom setting can be important, as children with PDD can readily be distracted by extraneous stimuli. The tendency of such children to rely on routines can be used effectively to help promote more systematic learning. Generalization of skills learned is particularly important since the child may have difficulties in applying skills learned in new settings. Speech and communication are a critically important aspect of an intervention programme. (27) Techniques to foster communication through non-verbal means such as sign-language, picture-exchange, and so forth can be used even in non-verbal children. (27) The use of such methods does not preclude the use of spoken communication.
For higher functioning and older individuals the acquisition and generalization of social skills are also important. Various methods can be used for teaching—for example, relative to problematic situations. Thus the use of rehearsal and social scripts may be indicated. Teaching must be explicit and can include a mix of small group and individual instruction with the use of naturalistic settings to encourage generalization whenever possible. For higher-functioning students, including those with Asperger's syndrome, this can include modelling of behaviours, videotaping for self-observation, role playing, and the use of individualized social stories. (79)
Behaviour modification techniques are helpful in increasing the frequency of desired behaviours while simultaneously diminishing problem behaviours. Typically, a functional analysis of the target behaviour is initially performed, and then a plan developed for prompting or decreasing the behaviour. (78) While there is general agreement that children with autism/PDD profit from a behaviourally based intervention, there is more controversy over the degree to which progress can be made; for instance, there have been some claims for dramatic improvement and even ‘cures' of autism.
There is no evidence that unstructured psychotherapy is useful in autism and related conditions. Structured and supportive psychotherapy may be appropriate for some carefully selected, higher functioning individuals, particularly if it focuses on rather explicit problem situations.
Pharmacological interventions are not curative, but they may provide considerable help with specific problematic symptoms. (80) Much of the available data on these agents is based on poorly controlled or uncontrolled studies or studies conducted with adults. The balance of potential benefits and risks should be considered, and informed consent obtained from parents or, whenever possible, the affected child.
Neuroleptics have been the most intensively studied agents in this population. (81) The main mechanism of action appears to be dopamine-receptor blockade. The agents may reduce maladaptive behaviours such as stereotypies, (81) but side-effects include sedation, irritability, and movement problems (including tardive dyskinesia). Recently, interest has centred on the newer atypical neuroleptics. (82)
Mood stabilizers and antidepressants have sometimes been used, given the increase in affective lability, anxiety, and depression in individuals with autism and PDDs. However, the response to antidepressants has been somewhat variable. Lithium and other mood stabilizers are sometimes used clinically, particularly if there is a strong family history of bipolar disorder, but there have been few controlled studies of these agents.
Selective serotonin-reuptake inhibitors (SSRIs) were of initial interest in autism, given the repeated reports of high group levels of serotonin in this population as well as of the high levels of repetitive behaviours observed in this group (i.e. reminiscent of those seen in obsessive–compulsive disorder). Several reports have suggested that, at least in adults, these agents may be helpful in lowering the levels of obsessive–compulsive-like behaviours, although activation is sometimes observed.(80) Studies of children have been less frequent, but there is some suggestion that they may also respond. (83)
Various other agents have been used in autism, including anxiolytics, b-blockers, clonidine, and naltrexone. Unfortunately, it is difficult to draw firm conclusions from the limited data available, but at present the clinical efficacy of these agents is not well established in this population. Following a very optimistic report there was considerable interest in fenfluramine, (84) although initial enthusiasm was tempered by the observation of various side-effects and a carefully controlled study noted a negative effect on learning. (85) Surprisingly few studies have systematically evaluated the use of stimulants in autism. However, the observation that these agents induce stereotyped behaviours in animals would suggest their potential for increasing levels of stereotyped behaviours.
At the moment, information on the prevention of autism and related PDDs is clearly quite limited. Apart from the association with two strongly genetic conditions (fragile X syndrome and tuberous sclerosis) no specific biological markers for autism have yet been found. It is possible, and indeed likely, that this situation may change dramatically over the coming decade as specific genetic markers for some form or forms of autism/PDD are identified.
1. World Health Organization (1992). International statistical classification of diseases and related health problems, 10th revision. WHO, Geneva.
2. American Psychiatric Association (1994). Diagnostic and statistical classification of diseases and related health problems (4th edn). American Psychiatric Association, Washington, DC.
3. Kanner, L. (1943). Autistic disturbances of affective contact. Nervous Child, 2, 217–50.
4. Treffert, D. (1989). Extraordinary people. Bantam, New York.
5. Clark, P. and Rutter, M. (1981). Autistic children's responses to structure and to interpersonal demands. Journal of Autism and Developmental Disorders, 11, 201–17.
6. Lincoln, A., Courchesne, E., Allen, M., Hanson, E., and Ene, M. (1988). Neurobiology of Asperger syndrome: seven case studies and quantitative magnetic resonance imaging findings. In Asperger syndrome or high functioning autism? (ed. E. Schopler, G.B. Mesibov, and L.J. Kunc), pp. 145–66. Plenum, New York.
7. Sparrow, S. (1997). Developmentally based assessments. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 411–47. Wiley, New York.
8. Rutter, M., Bailey, A., Simonoff, E., and Pickles, A. (1997). Genetic influences in autism. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 370–87. Wiley, New York.
9. Schopler, E., Andrews, C.E., and Strupp, K. (1979). Do autistic children come from upper-middle-class parents? Journal of Autism and Developmental Disorders, 9, 139–52.
10. Heller, T. (1908). Dementia Infantilis. Zeitschrift fur die Erforschung und Behandlung des Jugenlichen. Schwachsinns, 2, 141–65.
11. Volkmar, F.R. and Rutter, M. (1995). Childhood disintegrative disorder: results of the DSM-IV autism field trial. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 1092–5.
12. Volkmar, F.R. (1997). Childhood disintegrative disorder. In DSM-IV source book (ed. T.A. Widiger, A.J. Francis, H.A. Pincus, R. Ross, M.B. First, and W. Davis), pp. 35–42. American Psychiatric Association Press, Washington, DC.
13. Asperger, H. (1944). Die ‘autistichen Psychopathen' intramuscular Kindersalter. Archive für Psychiatrie und Nervenkrankheiten, 117, 76–136.
14. Wing, L. (1981). Asperger's syndrome: a clinical account. Psychological Medicine, 11, 115–29.
15. Wolff, S. and Barlow, A. (1979). Schizoid personality in childhood: a comparative study of schizoid, autistic and normal children. Journal of Child Psychology and Psychiatry, 20, 29–46.
16. Bishop, D.V. (1989). Autism, Asperger's syndrome and semantic-pragmatic disorder: where are the boundaries? British Journal of Disorders of Communication, 24, 107–21.
17. Ellis, H.D., Ellis, D.M., Fraser, W., and Deb, S. (1994). A preliminary study of right hemisphere cognitive deficits and impaired social judgments among young people with Asperger syndrome. European Child and Adolescent Psychiatry, 3, 255–66.
18. Klin, A., Volkmar, F.R., Sparrow, S.S., Cicchetti, D.V., and Rourke, B.P. (1995). Validity and neuropsychological characterization of Asperger syndrome: convergence with nonverbal learning disabilities syndrome. Journal of Child Psychology and Psychiatry, 36, 1127–40.
19. Volkmar, F.R., Klin, A., and Pauls, D. (1998). Nosological and genetic aspects of Asperger syndrome. Journal of Autism and Developmental Disorders, 28, 457–63.
20. Rett, A. (1966). Uber ein eigenartiges hirntophisces Syndröm bei hyperammonie intramuscular Kindersalter. Wein Medizinische Wochenschrift, 118, 723–6.
21. Hagberg, B., Aicardi, J., Dias, K., and Ramos, O. (1983). A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome, report of 35 cases. Annals of Neurology, 14, 471–9.
22. Rutter, M. (1994). Debate and argument: there are connections between brain and mind and it is important that Rett syndrome be classified somewhere. Journal of Child Psychology and Psychiatry, 35, 379–81.
23. Towbin, K. (1997). Pervasive developmental disorder not otherwise specified. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 123–47. Wiley, New York.
24. Volkmar, F.R., Carter, A., Grossman, J., and Klin, A. (1997). Social development in autism. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 173–94. Wiley, New York.
25. Wing, L. (1997). Syndromes of autism and atypical development. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 148–72. Wiley, New York.
26. Rutter, M. (1978). Diagnosis and definition of childhood autism. Journal of Autism and Childhood Schizophrenia, 8, 139–61.
27. Lord, C. and Paul, R. (1997). Language and communication in autism. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 195–225. Wiley, New York.
28. Kolvin, I. (1971). Studies in the childhood psychoses. I. Diagnostic criteria and classification. British Journal of Psychiatry, 118, 381–4.
29. Rutter, M. (1972). Childhood schizophrenia reconsidered. Journal of Autism and Childhood Schizophrenia, 2, 315–37.
30. American Psychiatric Association (1980). Diagnostic and statistical classification of diseases and related health problems (3rd edn). American Psychiatric Association, Washington, DC.
31. Volkmar, F.R. and Cohen, D.J. (1991). Debate and argument: the utility of the term pervasive developmental disorder. Journal of Child Psychology and Psychiatry,
32, 1171–2. 32. Rutter, M. and Schopler, E. (1992). Classification of pervasive developmental disorders: some concepts and practical considerations. Journal of Autism and Developmental Disorders, 22, 459–82.
33. American Psychiatric Association (1987). Diagnostic and statistical classification of diseases and related health problems (3rd edn, revised). American Psychiatric Association, Washington, DC.
34. Volkmar, F.R., Klin, A., Siegel, B., et al. (1994). Field trial for autistic disorder in DSM-IV. American Journal of Psychiatry, 151, 1361–7.
35. Fombonne, E. (1998). Epidemiology of autism and related conditions. In Autism and pervasive developmental disorders (ed. F.R. Volkmar), pp. 32–63. Cambridge University Press.
36. Volkmar, F.R., Szatmari, P., and Sparrow, S.S. (1993). Sex differences in pervasive developmental disorders. Journal of Autism and Developmental Disorders, 23, 579–91.
37. Howlin, P. and Goode, S. (1998). Outcome in autism and related conditions. In Autism and pervasive developmental disorders (ed. F.R. Volkmar), pp. 209–41. Cambridge University Press.
38. Rogers, S.J. (1996). Brief report: early intervention in autism. Journal of Autism and Developmental Disorders, 26, 243–6.
39. Deykin, E.Y. and MacMahon, B. (1979). The incidence of seizures among children with autistic symptoms. American Journal of Psychiatry, 136, 1310–12.
40. Volkmar, F.R. and Nelson, D.S. (1990). Seizure disorders in autism. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 127–9.
41. Waterhouse, L., Fein, D., and Modahl, C. (1996). Neurofunctional mechanisms in autism. Psychological Reviews, 103, 457–89.
42. Frith, U. (1989). Autism: explaining the enigma. Blackwell, London.
43. Ozonoff, S. (1998). Assessment and remediation of executive dysfunction in autism and Asperger syndrome. In Asperger syndrome or high functioning autism? (ed. E. Schopler, G. Mesibov, and L.J. Kunce), pp. 263–92. Plenum Press, New York.
44. Baron-Cohen, S. (1995). Mind blindness. MIT Press, Cambridge, MA.
45. Klin, A., Schultz, R.T., and Cohen, D.J. (2000). The need for a theory of theory of mind in action: developmental and neurofunctional perspectives on social cognition. In Understanding other minds (2nd edn) (ed. S. Baron-Cohen, H. Tager-Flusberg, and D.J. Cohen). Oxford University Press.
46. Frith, C. and Frith, U. (2000). The physiological basis of theory of mind: functional neuroimaging studies. In Understanding other minds (2nd edn) (ed. S. Baron-Cohen, H. Tager-Flusberg, and D.J. Cohen). Oxford University Press.
47. Minshew, N.J., Sweeney, J.A., and Bauman, M.L. (1999). Neurological aspects of autism. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 344–69. Wiley, New York.
48. Rutter, M. (1970). Autistic children: infancy to adulthood. Seminars in Psychiatry, 2, 435–50.
49. Chess, S. (1977). Follow-up report on autism in congenital rubella. Journal of Autism and Childhood Schizophrenia, 7, 69–81.
50. Gillberg, C.L. (1992). The Emanuel Miller Memorial Lecture 1991. Autism and autistic-like conditions: subclasses among disorders of empathy. Journal of Child Psychology and Psychiatry, 33, 813–42.
51. Rutter, M., Bailey, A., Bolton, P., and Le Couteur, A. (1994). Autism and known medical conditions: myth and substance. Journal of Child Psychology and Psychiatry, 35, 311–22.
52. Simonoff, E., Bolton, P., and Rutter, M. (1996). Mental retardation: genetic findings, clinical implications and research agenda. Journal of Child Psychology and Psychiatry, 37, 259–80.
53. Smalley, S.L., Tanguay, P.E., Smith, M., and Gutierrez, G. (1992). Autism and tuberous sclerosis. Journal of Autism and Developmental Disorders, 22, 339–55.
54. Woodhouse, W., Bailey, A., Rutter, M., Bolton, P., Baird, G., and Le Couteur, A. (1996). Head circumference in autism and other pervasive developmental disorders. Journal of Child Psychology and Psychiatry, 37, 665–71.
55. Anderson, G.M. and Hoshiono, Y. (1997). Neurochemical studies of autism. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 325–43. Wiley, New York.
56. van Acker, R. (1997). Rett's syndrome. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 40–93. Wiley, New York.
57. Trevathan, E. and Adams, M.J. (1988). The epidemiology and public health significance of Rett syndrome. Journal of Child Neurology, 3 (Supplement), S17–20.
58. Gillberg, C. (1994). Debate and argument: having Rett syndrome in the ICD-10 PDD category does not make sense. Journal of Child Psychology and Psychiatry, 35, 377–8.
59. Rutter, M. (1994). Debate and argument: there are connections between brain and mind and it is important that Rett syndrome be classified somewhere. Journal of Child Psychology and Psychiatry and Allied Disciplines, 35, 379–81.
60. Rett Syndrome Diagnostic Criteria Work Group (1986). Diagnostic criteria for Rett syndrome. Annals of Neurology, 23, 125–8.
61. Hagberg, B. (1985). Rett's syndrome: prevalence and impact on progressive severe mental retardation in girls. Acta Paediatrica Scandinavica, 74, 405–8.
62. Kozinetz, C.A., Skender, M.L., MacNaughton, N., et al. (1993). Epidemiology of Rett syndrome: a population-based registry. Pediatrics, 91, 445–50.
63. Hagberg, B. (1989). Rett syndrome: clinical peculiarities, diagnostic approach, and possible cause. Pediatric Neurology, 5, 75–83.
64. Riccardi, V.M. (1986). The Rett syndrome: genetics and the future. American Journal of Medical Genetics, 24 (Supplement 1), 389–402.
65. Evans-Jones, L.G. and Rosenbloom, L. (1978). Disintegrative psychosis in childhood. Developmental Medicine and Child Neurology, 20, 462–70.
66. Kurita, H. (1988). The concept and nosology of Heller's syndrome review of articles and report of two cases. Japanese Journal of Psychiatry and Neurology, 42, 785–93.
67. Volkmar, F.R. (1992). Childhood disintegrative disorder: issues for DSM-IV. Journal of Autism and Developmental Disorders, 22, 625–42.
68. Rutter, M. (1985). Infantile autism and other pervasive developmental disorders. In Child and adolescent psychiatry—modern approaches (ed. M. Rutter and L. Hersov), pp. 545–66. Blackwell, London.
69. Volkmar, F.R., Klin, A., Marans, W., and Cohen, D.J. (1997). Childhood disintegrative disorder. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 47–59. Wiley, New York.
70. Burd, L., Fisher, W., and Kerbeshian, J. (1989). Pervasive disintegrative disorder: are Rett syndrome and Heller dementia infantilis subtypes? Developmental Medicine and Child Neurology, 31, 609–16.
71. Corbett, J. (1987). Development, disintegration and dementia. Journal of Mental Deficiency Research, 31, 349–56.
72. Klin, A. and Volkmar, F.R. (1997). Asperger syndrome. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 94–122. Wiley, New York.
73. Miller, J.N. and Ozonoff, S. (1997). Did Asperger's cases have Asperger disorder? A research note. Journal of Child Psychology and Psychiatry, 38, 247–51.
74. Asperger, H. (1979). Problems of infantile autism. Communication, 13, 45–52.
75. Towbin, K.E. (1997). Pervasive developmental disorder not otherwise specified. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 123–47. Wiley, New York.
76. Lord, C. (1995). Follow-up of two-year-olds referred for possible autism. Journal of Child Psychology and Psychiatry, 36, 1365–82.
77. Harris, S.L. and Handleman, J.S. (1997). Helping children with autism enter the mainstream. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 665–75. Wiley, New York.
78. Schreibman, L. (1997). Theoretical perspectives on behavioral intervention for individuals with autism. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 920–33. Wiley, New York.
79. Gray, C.A. and Garand, J.D. (1993). Social stories: improving responses of students with autism with accurate social information. Focus on Autistic Behavior, 8, 1–10.
80. McDougle, C.J. (1997). Psychopharmacology. In Handbook of autism and pervasive developmental disorders (2nd edn) (ed. D.J. Cohen and F.R. Volkmar), pp. 707–29. Wiley, New York.
81. Campbell, M., Schopler, E., Cueva, J.E., and Hallin, A. (1996). Treatment of autistic disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 134–43.
82. McDougle, C.J., Brodkin, E.S., Yeung, P.O., Naylor, S.T., Cohen, D.J., and Price, L.H. (1995). Risperidone in the treatment of adults with autism or pervasive developmental disorder. Journal of Child and Adolescent Psychopharmacology, 5, 273–82.
83. Gordon, C.T., State, R.C., Nelson, J.E., Hamburger, S.D., and Rapoport. J.L. (1993). A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Archives of General Psychiatry, 50, 441–7.
84. Geller, E., Ritvo, E.R., Freeman, B.J., and Yuwiler, A. (1982). Preliminary observations on the effect of fenfluramine on blood serotonin and symptoms in three autistic boys. New England Journal of Medicine, 307, 165–9.
85. Campbell, M., Adams, P., Small, A.M., et al. (1988). Efficacy and safety of fenfluramine in autistic children. Journal of the American Academy of Child and Adolescent Psychiatry, 27, 434–9.