a prevalence study of autism in tuberous sclerosis

Journal of Autism and Developmental Disorders, Vol. 23, No. 2, 1993

A Prevalence Study of Aut ism in Tuberous Sclerosis 1

Ann H u n t 2 University of Oxford

Char le s Shepherd 3 Royal Hospital for Sick Children, Glasgow

An estimate of the prevalence of autism tn tuberous sclerosis (TSC) was made by interviewing the parents of 21 children between ages 3 and 11 ascertained during a previous population study of the condition in the West of Scotland. Five of the children (24%) were rated autistic and a further four (19%), all of whom were girls, had socially impaired behavior categorized as pervasive developmental disorder, without fulfilling all the DSM-III-R criteria for autism. One further boy had disruptive attention-seeking behavior that had excluded him from his normal school. The estimated prevalence from this study of autism in TSC is 1 in 4 children in general, and 1 in 2 of those with mental retardation. Tuberous sclerosis couM be a significant cause of autism and pervasive developmental disorders, particularly in girls.

I N T R O D U C T I O N

T u b e r o u s sclerosis complex , TSC, is a mul t i sys tem gene t i c d i s o r d e r tha t has long b e e n as soc ia t ed with aut is t ic behav ior . T h e cond i t i on shows a u t o s o m a l d o m i n a n t i nhe r i t ance bu t was t houg h t to have an a p p r o x i m a t e l y

1This work was supported by a grant from the Tuberous Sclerosis Association of Great Britain. The authors thank Jennifer Dennis for discussions during the preparation of the questionnaire and for collaboration on validating the recorded interviews.

2Address all correspondence to Ann Hunt, Section of Child & Adolescent Psychiatry, University of Oxford, Park Hospital for Children, Old Road, Headington, Oxford OX3 7LQ, England.

3present address: Craigavon Hospital, Portadown, Northern Ireland.

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0162-3257/93/0600-0323507.00/0 �9 1993 Plenum Publishing Corporation

324 Hunt and Shepherd

70% mutation rate when it was mainly diagnosed in severely affected individuals. However as more people are now diagnosed with minimal signs of TSC among these individuals' parents, the estimated mutation rate has decreased. In a study of tuberous sclerosis in the West of Scotland the minimum prevalence in children under the age of 10 was 1 in 12,000 (Samp- son, Scahill, Stephenson, Mann, & Connor, 1989). The birth prevalence will be higher as TSC is a very variable disorder and mildly affected individuals will only be ascertained after childhood. A point prevalence study on December 31, 1989, found 1 in 14,500 people with the condition in Olmsted County, Minnesota (Shepherd, Beard, Gomez, Kurland, & Whis- nant, 1991). In that paper 48% of those with tuberous sclerosis were estimated to have learning disabilities.

The condition shows genetic heterogeneity and at present there are thought to be gene locations at 9q34 and 11q23 (Connor, 1990). A faulty protein produces disordered cell differentiation and migration during the development of tissues, resulting in abnormal growths of tissue in many organs of the body. Those organs most notably affected are the brain, skin, kidneys, and heart. A striking characteristic of tuberous sclerosis is the vari- ability of expression of the condition, both in the position and number of lesions, producing a wide variation of physical and mental problems.

In the brain the abnormal growths are found as cortical and subcor- tical tubers, and as multiple subependymal glial nodules in the areas of the ventricle walls. The hard cortical tubers give the name "tuberous sclerosis" to the disorder and mainly have a structure of areas of disordered steUate neurons and areas of astrocytes which are distinct from one another (Ste- fannsson, Wollmann & Huttenlocher, 1988). The cerebellum is infrequently involved (Houser & Nixon, 1988) and slight to moderate ventricular dila- tion occurred in 75% of patients associated with calcified subependymal nodules in a study by Maki, Enomoto, Maruyama, and Maekewa (1979). Typically these nodules are located in or next to the caudate nucleus and thalamus, mostly on the outer walls of the frontal horn and body. In a study using MRI, Jambaque, et al. (1991) found cortical tubers in all re- gions of the cerebrum. These brain lesions in tuberous sclerosis can contribute to epilepsy, mental retardation, socially impaired behavior and overactivity.

The first description of autistic behavior in tuberous sclerosis (epiloia) was given by Critchley and Earl (1932) in a study of 29 people with TSC resident in mental subnormality hospitals. As this study predated Kanner's description (1943) of "early infantile autism" and looked at adolescent and adult patients, the behavior was categorized as a primitive form of catatonic schizophrenia. Critchley and Earl found patients difficult to examine physi- cally because of "a certain amount of negativism" and a highly charac-

Autism in Tuberous Sclerosis 325

teristic "peculiar type of motor restlessness." They describe "a primitive form of psychos is . . , the depth of psychosis is independent of the degree of intellectual defect, although the two processes are so inextricably inter- twined as to render impossible any accurate estimation of the part played by either in any given case . . . . " There was impairment of social contact, patients being described as "Solitary, silent and apathetic and liable to sudden brief outburst of motiveless e x c i t e m e n t . . , from the sudden fixation of their gaze upon nothing and from their air of l is tening-- again to noth- ingwintent ly and with a strange and alien smile, it seems possible that they undergo some crude hallucinatory experiences." Speech was abnormal, "they use very few words and may show echolalia and short perseverative repetition of phrases, or may become entirely mute." Stereotyped body movements were common, "All manner of bizarre attitudes and stereotyped movements occur, and these are most striking in the hands and fingers . . . . These movements appear to have some significance for the patients; they occur when the appearance of dissociation is most marked, and the eyes usually fixate the moving hand. Thus one boy has been seen with a rapt expression keeping up a highly complicated rapid movement of his right hand and slow and entirely different movement of the left." Formal psy- chometric testing was difficult, "One boy who had kept up an amazing se- ries of attitudinizations and elaborate movements of his hands, suddenly ceased and filled in the Wallin peg boards quickly and neatly, in thirteen and fourteen second respectively, to return at once to his movements, whence no further stimulation could arouse him."

After the definition by Kanner of the syndrome of autistic behavior, there were isolated cases reported of autism in children with tuberous sclerosis (Dick & Ziegler, 1967; Lawlor & Maurer, 1987; Mansheim, 1979; Taft & Cohen, 1971; Wakschlag, Cook, Hammond, Leventhal, & Hopkins, 1991). Fisher, Kerbeshian, Burd, & Kolstoe (1986) reviewed the people with TSC and pervasive developmental disorder (PDD) in North Dakota and concluded that with four known cases in a population of 652,695 there was a link between the two disorders. The remaining eight cases of tuberous sclerosis identified in North Dakota did not have PDD.

In 1983 Hunt reported a study of family aspects of tuberous sclerosis, which used a postal questionnaire completed in 1978-1979 by parents of 97 cases. The parents gave as their most pressing problem not the epileptic seizures or mental retardation but behavior problems including the lack of communication. In 1980--1981 Hunt therefore interviewed the parents of 90 children with tuberous sclerosis using a questionnaire that included Rutter's criteria for autistic behavior (Rutter & Hersov, 1977). The behavior questions used followed very closely those on social behavior in the HBS schedule (Wing & Gould, 1978), but because behavior was only


part of a wider study of children with TSC, there was not sufficient time to administer the complete schedule. However, these interview questions and a retrospective case-note study for all the children (Hunt & Dennis, 1987) found that 50% of the children showed autistic behavior at the age of 5, with a further child developing similar behavior after that age. Al- though infantile spasms, a form of early generalized epileptic seizures, were common in the sample, the autistic behavior also developed in a third of the children with other seizures, although not in the few children without seizures. The sample had been gathered from members of the Tuberous Sclerosis Association of Great Britain and included a high proportion, 83%, of children with learning difficulties. However the study did establish that children with tuberous sclerosis could need specialized help because of their autistic behavior as well as because of their learning difficulties. A study of the differences between people with tuberous sclerosis, with and without autism, might elucidate at least one cause for the behavioral syndrome.

It is necessary therefore to establish how common autism is in the population of people with tuberous sclerosis, not just among those who, as in the previous study, mainly have learning difficulties. The prevalence study of all known cases of TSC in the West of Scotland had ascertained 42% of people with normal intelligence, although it was recognized that the true figure would be higher, as children with the condition who had not developed either epileptic seizures or skin signs would not yet have been diagnosed. The parents of all the children 3-11 years old with tuberous sclerosis in the West of Scotland study were therefore questioned about their children's behavior to ascertain the prevalence of autism in tuberous sclerosis.

METHOD

The study was undertaken in 1989 and looked at the behavior of children with tuberous sclerosis, age 3 to 11 years on July 1, 1989. There were 21 children born in the West of Scotland between July 1, 1977 and July 1, 1986 who had at least one of the primary diagnostic features of the TSC complex (Gomez, 1988). In the full West of Scotland study there were 104 (55 male, 49 female) individuals with tuberous sclerosis. Of these, 58 had seizures and intellectual impairment, 32 had seizures with no intellectual impairment, and 14 had neither seizures nor intellectual impairment. In all cases intellectual impairment was associated with seizures.

Ascertainment of cases in the West of Scotland study was made through medical genetic, pediatric neurology, pediatric, neurology, derma-


tology, and mental handicap departments and through the Tuberous Scle- rosis Association. All the children found between ages 3 and 11 years had had seizures even if the seizures were no longer current. The occurrence of seizures in the sample is due partly to ascertainment of these cases through the pediatric neurology services and partly that seizures are one of the commonest early presenting features of tuberous sclerosis. All the 14 individuals who had no seizures were diagnosed with TSC when their children presented with seizures that were secondary to tuberous sclerosis. In 82 of the 104 cases in the West of Scotland study, the parents were examined for evidence of tuberous sclerosis. It would be unlikely that the small number of asymptomatic children between 3 and 11 years in the area would be ascertained. Symptoms other than seizures are rare in children of this age with tuberous sclerosis.

An estimate of the level of learning difficulties of the children was made from the type of education or health service resources received. When intellectual disability was present, generally children with severe disability had an IQ < 35 and children with moderate disability an IQ = 35-70. Assessments were not made of the intellectual ability of the normal children, but none had special education needs and the preschool children had development within normal limits on routine assessment. The development of all the children had been followed for at least 3 years.

When questionnaires for the earlier studies by Hunt (1978-1981) had been prepared there were few established diagnostic schedules for autism. For reasons of comparison in the study of tuberous sclerosis, it was felt to be important that similar questions were asked in this present study to those used in the earlier work on children with TSC. For both studies, semistructured questionnaires were prepared for interviews with parents. The questions were based on those in the HBS (Wing & Gould, 1978) schedule, and both the earlier face-to-face, and the present telephone interviews allowed the approach to be used of rephrasing questions until it was quite clear that (a) the question had been correctly understood and (b) that a rating could be made from the response. The answers were used in the 1980-1981 study (Hunt & Dennis, 1987) to elucidate socially impaired and autistic behavior, as well as overactivity and aggression. It was important at that stage to establish whether the socially impaired behaviors shown by children with TSC could be explained solely as a consequence of earlier infantile spasms, or, as was found, occurred also in children with no history of those particular epileptic seizures. To allow a direct comparison with the 13 Rendle-Short criteria for autism (Bruce, 1967) used in a study of children with earlier infantile spasms by Riikonen and Amnell (1981), the criteria chosen by Hunt and Dennis (1987) were questions on


socially impaired behavior that directly matched the Rendle-Short criteria. Rutter's criteria for autism were also applied.

In this 1989 study, for similar reasons of comparison with the results of the 1980-1981 interviews, the same 13 criteria for autistic behavior were used and a score of 7 or more indicated a child with autistic behavior. There were also questions about present seizures and medication, speech development and echolalia, onset of impaired social interaction, and non- compliant behavior. As overactive behavior can be concurrent with autistic behavior in younger children, parents were also asked about the child's level of activity, wandering, and unpredictability. In addition, problems with an established sleep pattern were included, such as difficulty in settling to sleep or persistent waking in the night, as it was also wished to get information on these problems in children with the brain lesions found in TSC.

The childrens' parents were contacted and all gave permission for the interviews. Because of the distance, the interviews were conducted by telephone, and permission sought for their recording for later analysis. Twenty parents were interviewed in this way, but 1 parent could not be contacted by telephone. This mother completed a printed version of the questionnaire by post.

Questionnaire sheets were briefly completed by the interviewer at the time of the interview in case the recording failed or the telephone line was poor. The full sheets were completed later by the interviewer from the recorded interviews. In a check for rater bias a colleague independently completed questionnaire forms from the recorded interviews. The questionnaire replies were then analyzed for criteria for autistic or socially impaired behavior. First the analysis used the 13 criteria for autism from the previous study so that a comparison could be made between children with tuberous sclerosis in the two groups. The same questionnaire replies were then analyzed in the terms of the DSM-III-R criteria for pervasive developmental disorder and in particular for autistic disorder to allow for comparison with more widely accepted criteria than the Rendle-Short criteria. The number of children who showed overactive and impulsive behavior was also noted.

Since infantile spasms are a known predisposer to later autistic behavior (Riikonen & Amnell, 1981), the history of these and later epileptic seizures was recorded from the Scottish prevalence study as was the estimated intelligence of the child.

RESULTS

There were 21 children with tuberous sclerosis ages 3 to 11 years included in the study. Questionnaires were completed on 20 children from


the telephone interviews, and 1 questionnaire was completed by post. There were 2 recordings that failed and could only be scored from the sheet completed at the time of the interview, leaving 19 that were completed by two raters. There were 13 criteria used for autism to enable comparison with the previous sample of children with TSC and a score of more than 7 was taken to indicate that autistic disorder was present. Of the 19 questionnaires separately rated, 13 had the same total number of criteria scored, and in 6 the total varied by no more than 2, but in no cases did this alter the diagnosis of autism. An analysis of interrater reliability was made using the ratings from the original recordings by the two raters of all 13 answers for the 19 children and this showed no significant difference between the 2 raters using Cochran's test, )~2(18) = 26.28. The same children were scored to be autistic on the answers rated by both raters. For the 2 recordings that failed, the analysis of the questionnaire completed at the time of the interview showed 1 boy with normal behavior and 1 boy, who although not autistic had attention-seeking disruptive behavior. The postal questionnaire revealed a girl with no problems of social response although slightly overactive. There was assessed to be enough data available to in- clude all 21 children in the study.

Five of the 21 children were rated to be autistic by fulfilling 7 or more of the 13 criteria for autism. The questionnaires were then evaluated against the broad DSM-III-R criteria for PDD. The same 5 children, 3 boys and 2 girls also satisfied over 8 of the 16 DSM-III-R criteria for autism (Table I). Three of the children had severe learning difficulties and 2 moderate. Early infantile spasms are associated with later autistic behavior, but although 3 of the autistic children had a history of infantile spasms, 2 did not. Two children had later complex partial seizures, and 2 had myoclonic seizures. Seizures were current for 3 children but had ceased for 2 girls at age 2 years. All the children were overactive during the day and 4 had problems settling to sleep, a 7-year-old was not asleep until between 11 p.m. and 1 a.m. and a 10-year-old who could still be awake at 2 a.m. (see Appendix).

There were a further 4 children, all girls, who could be rated as having socially impaired behavior that could be described as a pervasive developmental disorder but who did not fulfill DSM-III-R criteria for autistic disorder. All these girls had severe learning difficulties, and the 2 younger ones, age 4 and 6 years, did not walk. Two children had a history of infantile spasms, the other children having tonic or complex partial seizures. The 2 younger girls did not speak, but the older 2 had started to speak single words at 31/2 and 5 years, respectively (Appendix). The 2 immobile children could not be rated as autistic because of their limited repertoire of behaviors, but neither interacted with other people and both avoided


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eye contact. They were distressed by physical contact although one enjoyed rough play with her father. This behavior contrasts with that of an equally profoundly handicapped nonmobile girl (No. 11) who did not object to physical contact, and who made eye contact, although she often had a blank stare. She enjoyed company appropriately for her developmental level and would watch other children play and not ignore them. Details of the children rated to have pervasive developmental delay are given in Appendix.

There was 1 further boy who cannot be totally rated for socially impaired behavior as the tape failed to record completely and the rating had to be done from the information recorded on the questionnaire sheet at the time of the interview. He was nearly 9 years old and had unusual interaction with strangers and jumbled speech, but he did not fulfill criteria for autism. He attended a normal school, although at the time of the interview had been excluded for disruptive behavior. It was not really possible to rate his behavior by a telephone interview but it gave his father concern and appears to involve an attention deficit disorder (Case No. 10, Appen- dix).

The remaining children had normal social interaction. One, as previously described, was profoundly handicapped and 2 had moderate learning difficulties. These latter 2 children were rated as more active than other children of the same age by their mothers, but neither had unpredictable behavior that needed constant vigilance. The remaining 8 children attended normal schools and none had a history of infantile spasms. However all had experienced other seizures and 4 had current seizures. Although their social interaction and play was normal, 4 of the children were markedly overactive, with impulsive behavior (see Table I). Three of these children had current complex partial seizures, but the fourth child had only ever had one seizure at 16 months of age. His overactive behavior caused problems at school and could be rated as an attention deficit disorder (Case No. 20, Appendix).

It can be seen that, given the limitations of the questionnaires, 5 of the 21 children (24%) could be classified as having autistic behavior and a further 4 (19%) to have autistic traits or pervasive developmental disorder. There were 9 children with no learning disabilities, 4 with moderate learning disabilities, and 8 with severe or profound retardation. The autistic children all had some degree of learning disability, but there were children with equal disabilities who were not autistic. Similarly, seizures were not always current for the autistic children, having stopped, respectively, 4 and 8 years previously for 2 girls. Again, there were also children with normal intelligence and social behavior who did have intractable epilepsy.


In addition to socially impaired behavior, 11 of the children were reported to be overactive, 5 of whom were autistic and 1 who had pervasive developmental disorder. This behavior also occurred in 5 children attending mainstream education who were not autistic. Nine of the 11 overactive children had sleep problems such as difficulty in settling or waking every night.

DISCUSSION

There are obvious limitations in using a telephone interview of parents to establish criteria for autistic behavior, but the technique did enable more information to be gathered than from a postal questionnaire or a case-note review. Again, the direct wording used for DSM-III-R criteria was not used in this study, but the answers received were analyzed after- wards in the light of those criteria. But interviewing parents in daily contact with their children did allow for a better picture of behavior to be gained than that given in infrequent case notes. The information gained should therefore be regarded as an initial study of autism and TSC, and further work is needed using the standardized questionnaires now available and involving an established population of children with tuberous sclerosis, not just a group collected for research purposes.

From this study a relationship between autism and tuberous sclerosis is established with an estimated prevalence in one in four children with TSC. There were 12 children with moderate to profound learning disabilities of whom 5 were rated autistic, 4 showed pervasive developmental disorder, but 3 had no such behavioral criteria. So, although no children with normal intelligence in this sample had PDD, the presence of mental retardation in itself is not always associated with this behavior in TSC. Similarly with seizures, children with current seizures showed both the presence and the absence of the behavior although a history of seizures was present in all this sample. In the opposite situation (Case No. 5), one autistic girl had had no seizures for 8 years and was no longer on medication. Therefore, neither the presence of mental retardation nor the history or presence of infantile spasms nor current seizures are sufficient explanation for the autistic behavior found in children with TSC. Although none of the children with normal intelligence in this study were autistic, intelligence was estimated from schooling and the behavior in itself may be sufficient to depress the academic functioning of the children.

Parents of half the children in this study thought they were more overactive than other children of their age, wandering around most of the day and needing watching because of unpredictable behavior. This overactivity was shown both by autistic and nonautistic children and also by children


with a wide range of intelligence so it may well be related to the underlying deficits associated with tuberous sclerosis. Sleep problems are significantly associated with daytime hyperactive behavior in children with mental handicap (Quine, 1991) and are often mentioned in relation to autistic behavior. There are no criteria for sleep-disordered behavior in children included as a category in DSM-III-R although settling is mentioned in separation anxi- ety, a socially aware behavior unlikely to be associated with autism.

In this study there were 3 boys and 2 girls with autistic behavior among 10 boys and 11 girls with TSC. Among the 45 boys and 45 girls with TSC studied by Hunt and Dennis (1987) there were 24 boys and 22 girls rated to have autistic behavior (A. Hunt, personal communication, 1992). Autistic behavior in tuberous sclerosis appears to affect boys and girls equally and this differs from the normal ratio of 4:1 found in autism in general. Autism has various etiologies, and therefore it is important to remember the association with specific conditions such as tuberous sclerosis or untreated phenylketonuria whenever general studies of the genetics of the autism are made. Two or more children with autism in one family could be the result of TSC with minimal outward signs of the disorder. Tuberous sclerosis affects 1 in 10,000-12,000 children and, from this prevalence study, 1 in 48,000 children will have TSC and autism. As autism in general affects 4-5 children in 10,000, it seems possible that tuberous sclerosis could make a significant contribution, up to 5%, to epidemiological studies of autism. It could contribute a higher proportion of girls than boys as there are ap- proximately equal numbers of girls and boys affected by TSC unlike the ratio found in autism in general.

It cannot be assumed that population studies of autistic behavior ex- clude children with tuberous sclerosis as the diagnosis of the condition may not have been made in a young child. By the age of 5 the characteristic red facial rash, often used as a diagnostic sign, has not yet developed in the majority of children with TSC. White skin patches which can suggest the disorder are present in over 95% of children, but unless a search using an ultraviolet (i.e., Wood's) light is made they are often hidden by clothing. However, epilepsy in a young child with autism should be investigated for tuberous sclerosis. This is not just because the implications of the dominant genetic disorder for a family where the parents may be contemplating further children, but also because some of the other complications of TSC, such as brain or kidney tumors, may affect the child's future health.

The prevalence of autism in tuberous sclerosis must be related to the organic brain condition, in the way that epileptic seizures and mental retardation are related. There have been several biological abnormalities pro- posed as pathways that could lead to autistic behavior and it is relevant to consider what is known about TSC in relation to these pathways. Among


these are enlarged ventricles, cerebellar involvement, and damage to the dopamine system of the brain. Enlarged ventricles may do no more than reflect structural abnormalities and atrophy.

The dopamine system projects not only to areas of the cortex, such as the frontal and temporal lobes, but also through the basal ganglia (Cole- man & Gillberg, 1985). The subependymal calcified lesions shown on CT scans of people with tuberous sclerosis are found in areas of the basal ganglia, such as the caudate nucleus and amygdala. A MRI study of noncalcified lesions in the brains of 23 children with TSC by Jambaque et al. (1991) included 6 children who were severely mentally retarded and autistic. The cortical lesions of these 6 children were large bifrontal and posterior tubers. In contrast only single and unilateral frontal tubers were found in 10 retarded but nonautistic children, but they also had other unilateral and bilateral tubers in other areas of the cortex. The children with normal intelligence and behavior had isolated cortical tubers mainly in the parietal and posterior lobes. As CT scans detect calcified lesions and MRI noncalcified lesions in TSC it is possible to have abnormal growths in both the limbic and frontal cortex areas in the same person. Although the exact relationship of brain lesions to epilepsy, development, and behavior in TSC has yet to be understood, the number and positions of the lesions are ob- viously important. Further study of these relationships in TSC might also contribute to a wider understanding of autism and pervasive developmental disorders.

APPENDIX

Case Histories of the Nine Children with Pervasive Developmental Delay

Case No. 1. A 6-year-old boy had severe learning difficulties and several myoclonic and other seizures every day. He took 10 mg of nitrazepam a day but his seizures had never been controlled. He had begun to babble at 2 years old but had no useful words at age 6. He would point and make noises to get things he wanted. He actively avoided eye contact and his mother said she had to hold his head to get his attention when she was trying to speak to him. He would remain aloof in a group and ignore other children's play. He ran around most of the day, sometimes in circles, and his mother thought him overactive for his age as he needed watching all the time because of unpredictable behavior. He had an obsession with water play and would only concentrate for a short time on puzzles before he began to throw them around. He had no idea of danger and his mother felt he would go with any stranger.

Autism in Tuberous Sderos is 335

Case No. Z A 7-year-old boy had moderate learning difficulties. He had a history of febrile convulsions, but he was not on regular medication as his seizures could be months apart. He had some meaningful speech which had started just before age 3 when his speech "came in a burst." He did not interact with other people and would not speak to strangers even to obtain current needs. However with his mother he was very de- manding and would have tantrums if he did not get things immediately. He would stay aloof in a group and ignored other children's play, although he might play with one child. He was very attached to padlocks and keys, which meant that house keys had to be kept hidden, His play lacked imagi- nation, he "didn't know what toys were for" and he preferred to play with padlocks or hammer in nails. He liked routine and resisted attempts to get him to learn new tasks. He was overactive, settling to sleep between 11 p.m, and 1 a.m., wandered around most of the day, and had to be watched continuously because of unpredictable behavior.

Case No. 3. A 7-year-old girl had severe learning difficulties and seizures that had been controlled by carbemazepine for 4 years. She started to speak just before age 5 years, and about 3 months before the interview had begun to put two words together. Her mother said that most of her words now had meaning instead of being echoed phrases, and that she could now point and ask for objects. Her mother had noticed a similar change in her social response over the same period, and she would now occasionally glance at people and interact to obtain her needs, whereas before she actively turned away from eye contact and was "in her own little world." She was beginning to go to her teacher for a comfort but previously had pulled away from physical contact. She would remain aloof in a group and ignore other children apart from running around together. She would not play with toys and preferred listening to music or carrying musical objects around. The family had recently moved house and she was now unable to reestablish a sleep pattern, not settling until 10-12 p.m. unless her mother slept with her. During the day she wandered around, not sitting and sometimes ran around in circles.

Case No. 4. A 9-year-old boy had severe learning difficulties and was in residential care because of the problems his behavior had caused in the family. His myoclonic seizures were controlled by carbemazepine but he still had absence attacks. He had no speech and although he was mainly aloof and indifferent to other people, his mother felt he could now differ- entiate between strangers and familiar people. He did not take much in- terest in what was going on around him, and did not join in at all with other children's games, giving brief glances to people around him. To obtain his needs he would not point but would take people by the hand and stare in the direction of what he wanted. He would get excited by knobs


that could be turned, particularly if music was the result, and would hold musical toys against his face. Although the word "autism" had not been mentioned, his mother said he did "hand movements like an autistic child." His mother felt that the routine of the residential school suited him, but he was still resistant and uncooperative when she tried to teach him some- thing new.

Case No. 5. A 10-year-old girl had moderate learning difficulties and seizures had stopped at age 2 and antiepileptic medication that had ceased at age 5. She had no speech until age 9 but had begun phrases such as "jacket on" in the past year. She did not intereact with anyone and would pull away from people other than close relatives, but had a recognized fear of white coats, so that the dentist would take his coat off before he treated her. She was overactive, wandering during the day, and sometimes be awake until 2 a.m., particularly on stormy nights as she was terrified of the wind outside. She ignored children but would search adults' bags. If a stranger spoke to her she would look and giggle at them. She wore a hearing aid but her mother felt her hearing was almost normal, although if there was a lot of noise she would scream and hold her hands over her ears. Although she had little speech, she had a good memory for tunes from the television which she hummed all day. Her main occupation was looking through mail order catalogues, and she would not play with toys. She had received a doll and pram at Christmas, but would only throw the doll out of the pram.

Case No. 6. A 4-year-old girl had profound learning difficulties and complex partial seizures that were uncontrolled by clonazepam. She had no speech or babble and her mother felt she did not know the difference between people. She was unable to walk, and up to 6 months earlier had screamed if cuddled, even by her mother. She ignored other children and looked past people. Because of her limited abilities she did not hold toys and her main occupation was listening to taped music.

Case No. 7. A 6-year-old girl had profound learning difficulties and seizures that had decreased in the past year. She had no speech and could not walk and was described by her mother as being always withdrawn. She would actively avoid physical contact with people and screamed if her legs were moved. She would turn her head away to avoid eye contact and remain aloof in a group. She did however enjoy rough play with her father and being thrown in the air and could eye-point to her mother to express her needs.

Case No. 8. A 9-year-old girl had severe learning difficulties and seizures every day. She began to talk at 31/2 years and by 9 used single words and echoed phrases. She would interact appropriately with people but usually avoided looking at them. She ignored other children's play, her own


play being limited by her developmental level, overactivity, and inattention. Changes in her environment had to be introduced gradually and she had no idea of danger.

Case No. 9. An ll-year-old girl had severe learning difficulties and had experienced 4 years free of seizures a few months before interview. Speech had begun at 5 years of age, and she began to put two words together around age 61/2. She had been very overactive when younger and could still be awake until 1 a.m. and then wake again at 5 a.m. When young she had slept with a net over her cot to prevent her wandering around the house in the night. At I1 she was described as becoming more sociable although she still avoided looking at people. She was just beginning to approach people and take part in play with other children. She was obsessively attached to one doll which, since it had to remain intact, had become an amalgamation of two other dolls over the years.

Case Histories of Two Boys Whose Behavior Caused Problems in Mainstream Education

Case No. 10. An 8-year-old boy had attended a mainstream school. His seizures had been controlled a year previously by carbemazepine. His speech, which had started at age 2, was described by his father as "jumbled" and was not normal for his age. He was overfriendly with strangers and had inappropriate interaction with them, as he would stare into their eyes while "throttling" them. Until age 6 he had been very quiet, but his father said that for the previous 2 years he had been an attention seeker. He was overactive, moving around most of the day, and would wake from sleep every night. His father had been asked to remove him from school a few days previously because of his disruptive behavior in the classroom. He could not be left alone because of unpredictable behavior that would make him the center of attention. He could play with other children but would wreck their games if he did not get his own way and would often break toys. He had an obsessive habit of "rubbing himself off on the floor." His favorite activity was computer games, and his father said he was cooperative if he thought he could do a task, but would not try any activity that he felt he could not succeed at the first time.

Case No. 20. A 10-year-old boy had one febrile convulsion only at age 16 months and normal intelligence. He made normal social approaches and played with other children, but he was said to usually avoid eye contact. He had a marked problem with wandering around which caused difficulties at school and his mother had wondered if he was deaf quite a few times. At 10 he was still attached to some cuddly toys and just beginning to make


models with Lego. His favorite activity was to listen to the same tapes he had had for 5 years. Although he was aware of the danger of traffic, when his attention lapsed he tended to run straight across roads.

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a prevalence study of autism in tuberous sclerosis

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