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Eur Child Adolesc Psychiatry (2005) 14:183–190 DOI 10.1007/s00787-005-0443-1

Petrus de Vries Ayla Humphrey Deborah McCartney Penny Prather Patrick Bolton Ann Hunt and the TSC Behaviour Consensus Panel

Accepted: 16 September 2004

P. de Vries · A. Humphrey · D. McCartney · P. Bolton Developmental Psychiatry Section University of Cambridge Cambridge, UK P. Prather Departments of Neurology and Psychiatry Massachusetts General Hospital & Harvard Medical School Boston (MA), USA P. Bolton Child & Adolescent Psychiatry Department and MRC Centre for Social, Genetic and Developmental Psychiatry Institute of Psychiatry London, UK A. Hunt () Tuberous Sclerosis Association Church Farm House Church Road North Leigh Witney OX29 6TX, UK E-Mail: [email protected]

ORIGINAL CONTRIBUTION

Consensus clinical guidelines for the assessment of cognitive and behavioural problems in Tuberous Sclerosis

■ Abstract Tuberous Sclerosis (TSC) is a genetic disorder characterised by abnormal growths in a wide range of organs. In the brain, abnormalities of differentiation, proliferation and migration can produce a range of neuropsychiatric features such as mental retardation, autism and ADHD. Although these manifestations are not diagnostic of the disorder, cognitive and behavioural features are often of greatest concern to families yet limited clinical assessment and interventions are currently offered. A consensus panel at a TSC Brain/Behaviour workshop recommended that the cognitive and behavioural profiles of individuals with TSC should be assessed at regular intervals in a planned fashion in accordance with the difficulties associated with the disorder. Evaluations should in-

Introduction “. . . behavioural disorders are underrecognised, underdiagnosed and often not treated in TSC” Behavioral and Psychiatric Panel, Annapolis TSC Consensus Conference, 1998

■ Key words Tuberous Sclerosis – clinical guidelines – cognition – behaviour

two-thirds of cases, diagnosis is made when an infant presents with epileptic seizures in the first year of life [10]. In the CNS, features include cortical tubers (CT), subependymal nodules (SEN), subependymal giant cell astrocytomas (SEGA) [10] and widespread grey and white matter abnormalities [32]. Epilepsy is a major manifestation and an array of behavioural and neuropsychiatric manifestations are also associated with TSC such as mental retardation, specific learning disabilities, autism spectrum disorders and ADHD [2–7, 9, 12, 13, 25, 27, 31]. Even though these neuropsychiatric manifestations are not diagnostic features of the disorder [35], the cognitive and behavioural features of the

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Tuberous Sclerosis (TSC) is a multi-system genetic disorder caused by mutations in the tumour suppressor genes, TSC1 or TSC2 [10, 36]. It is characterised by abnormal growths in a wide range of organs including the skin, kidneys and central nervous system [10]. In over

clude the use of standardised neuropsychological and behavioural tools as appropriate to the age and developmental level of the individual assessed. These cognitive and behavioural profiles should be incorporated in the overall formulation of the needs of the person with TSC to plan educational, social and clinical management strategies. Assessments should be documented so that individual longitudinal progress can be monitored. The paper outlines the problems associated with TSC, the purpose of recommended assessments, developmentally appropriate stages for assessment, and identifies specific areas that should be targeted for assessment.


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European Child & Adolescent Psychiatry (2005) Vol. 14, No. 4 © Steinkopff Verlag 2005

disorder are often of greatest concern to families [19]. It is a worldwide feature that there is often little or no clinical assessment or intervention offered for problems in these areas, in spite of the fact that these problems can lead to significant difficulties in daily life, and disrupt educational and occupational progress [8, 24, 31, 39]. In 1998, following a consensus meeting in Annapolis, Maryland, clinical guidelines were drawn up for the diagnosis [35] and assessment [34] of individuals with TSC. These guidelines [34] included cursory advice on cognitive and behavioural evaluations. ‘Neurodevelopmental Testing’ was recommended at diagnosis and at school entry. No specific guidelines were given on which behavioural and cognitive aspects to assess, and no recommendations were made to repeat cognitive and behavioural assessments. Since the 1998 consensus conference, significant progress has been made in delineating the cognitive and behavioural profiles of children and adults with TSC. With the financial support and endorsement of the Tuberous Sclerosis Association (UK) and the TSAlliance (USA), a consensus conference was convened in 2003 in Cambridge (UK) with the aim of producing guidelines for cognitive and behavioural assessments of individuals with TSC incorporating up-to-date evidence from research studies. The expert panel included child and adolescent psychiatrists, neuropsychologists, clinical and research psychologists, paediatric neurologists, special needs educators and other researchers familiar with clinical issues in TSC. In addition, the panel incorporated parents, carers and individuals with TSC. The paper summarises in two sections the consensus guidelines produced by the panel. Firstly, frequently encountered cognitive and behavioural difficulties associated with TSC are outlined and evidence for such difficulties presented to provide the framework and reasons for the consensus views of the expert panel (for a detailed review, see Prather and de Vries [31]). Secondly, the consensus recommendations for assessment are given with the suggested developmental stages and age ranges for assessments. Also given are the purposes of the assessment at these ages and specific areas to assess. The guidelines presented here are ultimately a con-

sensus of expert opinion based on the best available evidence in the field. All peer-reviewed publications relating to cognition and behaviour in TSC were used in the preparation of these guidelines. These included postal surveys, population-based studies, experimental casecontrol studies, extended kindred and single-case studies. Less accessible research not published elsewhere such as conference abstracts and doctoral theses were also utilised where deemed appropriate. Unlike other disabling conditions such as Down’s syndrome or Fragile-X syndrome, many aspects of cognition and behaviour in TSC have received little systematic research so far. Where appropriate, anecdotal evidence was, therefore, also incorporated by the expert panel to provide balanced clinical guidelines. The guidelines are intended as advice to clinicians who have individuals with TSC in their care, and as guidance to individuals, parents and carers about stages when assessments should be sought.

Cognitive and behavioural difficulties in TSC Tuberous Sclerosis is associated with a range of psychopathologies and cognitive deficits in individuals with and without mental retardation, as indicated in several studies [2–7, 9, 12, 18, 20–23, 27]. Table 1 summarises the spectrum of such difficulties in TSC. The range of behavioural problems include sleep disturbance [23], aggressive behaviours [21], specific phobias [38], self-injury, temper tantrums, depressed mood and anxiety [7, 19, 30]. In particular, there is strong evidence for high rates of ADHD (Attention Deficit Hyperactivity Disorder) [4, 5, 9], childhood autism [2, 9, 22], autism spectrum disorders and complex co-morbidity of developmental disorders [7, 9, 25]. Similar to the physical manifestations of TSC, there is great variability in the occurrence of these problems between individuals, even in monozygotic twins [17, 37]. Developmental disorders, socially unaware and disruptive behaviours predominate presentations in childhood and adolescence [7]. In adulthood, high rates of anxiety symptoms and depressed mood are reported [7,

Table 1 Cognitive and behavioural problems associated with Tuberous Sclerosis Cognition

Behaviour

Global cognitive deficits: mental retardation (WHO)/learning difficulties Specific cognitive deficits: Social-communication deficits Receptive and expressive language deficits Attentional deficits (selective attention, sustained attention and attentional switching) Executive deficits (planning, poor sequencing, perseveration) Memory deficits (working memory, episodic memory) Motor deficits Motor abnormalities (fine motor, gross motor, movement disorders)

Autism, Asperger’s and other autism spectrum disorders (ASD) ADHD and related disorders Aggression, rage outbursts and temper tantrums Negativity (temporary resistance to change) Emotional lability Depressive disorders Anxiety disorders Sleep disorders Epilepsy-related psychotic disorders


P. de Vries et al. Cognitive and behavioural guidelines for TSC

30, 37, 38]. There are case reports of manic illness [28] and of psychotic presentations [14–16], but no recent, clear systematic data are available to add to these reports. Significant research evidence in recent years has expanded knowledge of likely cognitive profiles of individuals with TSC. Intellectual abilities seem to have a bimodal distribution with individuals either functioning within the normal range or exhibiting moderate to profound handicaps. This was shown in an epidemiological study, where 55 % of individuals with the disorder had an IQ in the normal range (> 80), while about 30 % had global intellectual ability in the severe to profoundly impaired range (IQ < 21) [27].A longitudinal study of early cognitive development in a clinic-based sample of infants with TSC demonstrated that intellectual deficits are frequently apparent by one year of age and that the deficits tend to be stable and persistent in so far as the children in the study did not show any evidence of ‘catch-up’ in development by 30 months of age [18]. In some children with TSC, developmental outcome and progress may be correlated with the severity of seizure disorder and its control [2, 26, 27]. Those with intellectual impairments are more likely to have autism spectrum disorders [2, 7] or disruptive behaviours [5, 7, 21], but neither mental retardation nor epilepsy are necessary or sufficient to explain the over-representation of these behavioural disorders [5, 7, 31]. There is a high prevalence of significant language delay, even in those with normal intelligence [7, 31]. Among children and adults with TSC who have normal intelligence, there is increasing evidence of specific cognitive deficits in attentional skills [4–7] and executive skills [3, 5, 12, 31]. Even when children and adults with TSC do not meet diagnostic criteria for ADHD (such as impulsivity or hyperactivity), there is increasing evidence that they can show specific attention deficits and impaired goal-directed behaviour associated with executive control processes [5, 31]. Individuals who show deficits in executive control processes may be inefficient and even inept in managing tasks that require planning, organisation, monitoring and judgement [31]. There is evidence that memory skills may also be impaired in normally intelligent adults with TSC, particularly in retrieval of encoded memories [33]. No systematic studies of scholastic or occupational performance have so far been reported. Panel members representing the patient organisations however described significant difficulties in scholastic performance such as in reading, writing and arithmetic. There were also reports in adults of difficulties in occupational functioning, such as in establishing a career or vocation, and in the ability to ‘multi-task’ in the workplace. Clinicians and family care workers report very high rates of low self-esteem, the high burden of care and stress on families [24] and the fear of alienation of siblings, rela-

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tives and friends [39, 40]. In some areas, difficulties are reported in obtaining appropriate services from statutory and non-statutory agencies such as educational authorities, social services departments, health care professionals or insurance companies [11] due to the lack of understanding of the problems specific to TSC which have been identified by research.

Consensus statement ■ Rationale Research has demonstrated that TSC is a brain disorder with a high prevalence of cognitive and behavioural difficulties. Some of these difficulties, such as autism spectrum disorders or ADHD, will have clear social manifestations and require intensive interventions and considerable support. Others, such as attention or memory deficits, can be easily missed in a normally intelligent child. Research in this general area has shown that quite severe educational problems can be caused if the deficits are not identified and treated [29]. Applying these findings, it is important to know if such difficulties are present or not in any one individual with TSC. Regular and well-timed surveillance to check for emerging problems, backed up by detailed and appropriately tailored assessment for problems known to be associated with TSC, can enable a child to be offered, from the beginning, an individual remedial programme if required. It can never be good practice to put such a child or adult, without assessment, into a situation where they fail and only after failure assess them and offer help. Such an approach will maximise the chances of success and will potentially minimise the risk of added complications developing. This will avoid not only expensive and protracted intervention once a problem has developed, but will also prevent emotional trauma induced in a child or adult who fails.

■ Consensus recommendation I: Perform regular assessment of cognitive development and behaviour to identify and treat emerging difficulties and to establish a baseline for evaluating any changes in developmental trajectory The cognitive and behavioural profiles of children, adolescents and adults with Tuberous Sclerosis should be assessed at regular intervals in a planned, co-ordinated fashion with due regard for the breadth and depth of difficulties associated with the disorder. Assessments should be tailored to the presentation of problems in each individual and should be performed at the recommended ages in order to identify and address problems as they emerge, rather than after they have become man-


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ifested as abnormalities in development or adjustment. The earlier assessments up to school entrance should be routinely conducted in order to identify developmental and behavioural impairments that otherwise can be difficult to identify in young children and in order to establish a baseline measure against which any future changes may be evaluated. The recommended assessments at each age may need to be supplemented by further assessments if new clinical concerns emerge. Evaluations should use neuropsychological and behavioural tools appropriate to the developmental level of the individual assessed and these results should be interpreted within the wider clinical picture. It may not be necessary or appropriate to assess for every area of difficulty in every individual at every age. For instance, whereas global cognitive, motor and language development will be very important in babies and young children, emotional problems and skills needed for independent living will be more relevant to adolescents and adults. Assessment of the various areas will need different professionals as appropriate, such as developmental or community paediatricians, speech and language therapists, clinical or educational psychologists and psychiatrists in child and adolescent, adult and learning disability services. Cognitive and behavioural profiles should be incorporated, through the local multidisciplinary team, into the overall formulation of the needs of the person with TSC in order to formulate educational, social or clinical management statements and strategies. Information from assessments should be documented carefully to enable a review of the longitudinal progress of the individual with TSC.

■ Consensus recommendation II: Perform a comprehensive assessment in response to changes in cognitive development or behaviour to identify and treat the underlying causes of neurobehavioural change Changes in behaviour (e. g. increased aggression, withdrawal or change in sleep patterns), regression in development (e. g. loss of language or motor skills), deterioration of academic or vocational abilities or changes in physical manifestations (e. g. change in seizures, vision) should always be assessed and appropriately investigated. Regression and deterioration of functional abilities are not characteristics of the disorder, but may result from a range of biological, psychological and social factors such as seizures, pain, renal failure, medications, onset of a psychiatric illness or changes in the routine or environment of an individual with severe learning difficulties. In a small but significant minority of individuals, subependymal giant cell astrocytomas (SEGAS) may develop and produce complications either through invasion of surrounding cerebral tissue or through blockage

of the flow of cerebrospinal fluid through the foramen of Munro and the precipitation of pressure hydrocephalus. In such circumstances, there may be an associated deterioration in behaviour and intellectual ability or, potentially, the emergence of specific cognitive impairments. Investigations should, therefore, include a comprehensive physical and neurological review, functional analysis of behaviour, neuropsychological evaluation and appropriate special investigations such as biochemical profile, EEG and MRI.

■ Consensus clinical guidelines The consensus clinical guidelines for routine cognitive and behavioural assessments are presented in Table 2. The guidelines recommend assessments at set stages. For each assessment stage, the age range during which the assessment should be performed is given. The general purpose of assessments is outlined. Specific concerns to pay attention to are also listed for each stage. Even if an assessment is within normal limits, re-assessment should be performed at the next recommended stage when the individual is progressing into a new educational or social environment. Any subtle deficits identified should be recorded and taken into account by educators, families and other relevant professionals should problems arise.

■ Neuropsychological testing It is recognised that a wide range of neuropsychological tests are in general use in different countries, that some will be routine in pre-school or school settings, and that other neuropsychological tests will be more specialised tools derived from research studies. Specific tests are, therefore, not ‘prescribed’ to investigate particular cognitive domains, as these will depend on local resources and preferences. However, the areas of potential difficulty will not vary and it is important that these are assessed appropriately. A list of neuropsychological tests used in specialist TSC clinics is available through the Tuberous Sclerosis Association (TSA) (www.tuberoussclerosis.org) and the Tuberous Sclerosis Alliance (www.tsalliance.org).

■ Behavioural assessment The clinical diagnosis of psychiatric disorders should be made according to established international diagnostic criteria such as ICD-10 [41] and DSM-IV [1]. A range of supplemental tools such as interviewer-based schedules, observational schedules and behavioural rating scales are available to aid the diagnostic process. A list of be-

Birth – 12 months

1 year – 2 years 11months

3 years to school entry

6 years – 8 years

9 years – 12 years

13 years – 16 years

Toddler

Pre-school

Early school years

Middle school years

Adolescence

Age range for assessment

Infancy

At diagnosis

Assessment stage

Determining individual needs and the support required for transition into adult life

Complete review of child’s abilities, specific learning difficulties and behavioural problems in preparation for the transition to secondary education

Monitoring the child’s ability to make appropriate educational progress

Evaluation of cognitive and behavioural profile to ensure the provision of appropriate educational programmes

Initial assessment of cognitive and behavioural profile To perform a baseline assessment for regular monitoring of development To identify early developmental delay or developmental disorders

General purpose of assessment

Global cognitive abilities Specific cognitive skills: Attentional-executive skills Vocational assessment with knowledge of cognitive strengths and weaknesses Adaptive behaviour and daily living skills

Attentional-executive skills

Memory

Visuospatial skills Motor skills Global cognitive abilities Specific cognitive skills: Receptive and expressive language Social communication skills

Social communication skills Memory Attentional-executive skills

Specific cognitive skills: Receptive and expressive language

Visuospatial skills Motor skills Global cognitive abilities

Global cognitive ability and adaptive behaviours Specific skills: Gross and fine motor skills Social-communication skills Global cognitive ability Specific cognitive skills: Receptive and expressive language Social communication skills Attentional-executive skills

Global standardised assessment of infant development

As listed for chronological age

General areas to assess

Poor judgement, decisionmaking

Subtle deficits of socialcommunication, unusual interests Poor short-term memory, episodic memory Planning, organisational abilities, multi-tasking difficulties

Rote learning difficulties Selective attention, sustained attention difficulties

Poor expressive language and word retrieval

Poor bilateral co-ordination Best time to establish baseline to assess whether specific cognitive skills and scholastic performance is discrepant from global intellectual abilities

Poor expressive language Poor reciprocity, peer interaction Poor regulation of affect and impulse

Uneven profile of abilities

Quality of eye-contact, joint attention, reciprocity

Impact of seizure onset and treatment on development

*Areas of particular concern in TSC

Depressive disorders Anxiety disorders Peer problems

Asperger’s Syndrome Peer problems Scholastic difficulties (reading, writing, spelling, mathematics)

Specific scholastic difficulties (reading, writing, spelling, mathematics) ADHD and related disorders Peer problems Aggressive behaviours

Autism and ASD ADHD and related disorders Self-injurious behaviour

Autism and Autism Spectrum Disorders (ASD) Severe aggressive outbursts Severe sleep problems

*Behavioural and learning problems of particular concern in TSC

Table 2 Consensus guidelines for cognitive and behavioural assessments in Tuberous Sclerosis. The table shows the regular timepoints for assessment of all individuals with TSC


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Depressive disorders Anxiety disorders Epilepsy-related psychotic disorders

havioural rating scales used in specialist TSC clinics is available through the Tuberous Sclerosis Association (TSA) (www.tuberous-sclerosis.org) and the Tuberous Sclerosis Alliance (www.tsalliance.org).

18 years + Adults (follow-up)

ASD autism spectrum disorders; ADHD attention deficit hyperactivity disorder * Many features listed in these columns can present at any age, but are listed here at stages most commonly associated with the emergence of such difficulties in TSC

Pay particular attention to change in cognitive abilities, vocational performance and behaviour

■ Post-assessment interventions

Dependent adults: Annual review of social care needs and support Independent adults: Vocational advice Genetic counselling as appropriate Review if problems arise

Global cognitive abilities Specific cognitive skills: Attentional-executive skills Memory 18 years + Adults

Newly diagnosed adults: assessment of cognitive, behavioural and vocational profile, determining biopsycho-social needs Monitoring for emergence of psychiatric problems or changes in existing cognitive and behavioural difficulties

Age range for assessment Assessment stage

Table 2 Continues

General purpose of assessment

General areas to assess

*Areas of particular concern in TSC

Difficulty with integrational skills Working memory, episodic memory problems Pay particular attention to change in cognitive abilities or behaviour

Depressive disorders Anxiety disorders Epilepsy-related psychotic disorders


*Behavioural and learning problems of particular concern in TSC

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These clinical guidelines do not present information on specific post-assessment interventions, but, if specific difficulties are identified at any of the assessment stages, the child or adult should be managed or referred as clinically appropriate. Management strategies are likely to involve a range of specialities and multi-agency involvement. Table 3 lists a range of possible outcomes of neurobehavioural assessments.

Conclusion Guidelines previously established for the assessment of the clinical manifestations of TSC included very little detailed advice on neurodevelopmental testing. However, the growing body of literature substantiates the very high prevalence of cognitive and behavioural problems in individuals with TSC that warrants as much emphasis on assessment and treatment as the physical problems. The guidelines presented here offer advice on the assessments that should be performed at various stages in a child or adult’s life in two broad areas: firstly, cognitive assessments to enable maximum support to be given for future cognitive development; and, secondly, behavioural assessments to diagnose problems that require psychiatric or psychological intervention. The stages when assessments are recommended are common to all children and adults with TSC. However, the tests administered, the subsequent educational programmes developed and any clinical treatment offered should remain tailored to the individual, their age and the local and national context. The guidelines recommend areas that should be targeted in the context of TSC, but are not meant to imply limiting assessments only to those areas. The consensus panel currently recommends the use of remedial programmes and clinical treatments as appropriate for non-TSC individuals with similar presentations, due to the lack of TSC-specific treatment studies. Clinical trials of pharmacological and non-pharmacological interventions are urgently required to provide evidence for best practice in the management of cognitive and behavioural problems in TSC.


P. de Vries et al. Cognitive and behavioural guidelines for TSC Table 3 Possible outcomes of neurobehavioural assessment of individuals with Tuberous Sclerosis

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1. Arrange further detailed evaluations (including functional analysis of behaviour, physical review and special investigations) 2. Enrol child in community programme for early intervention 3. Develop specific therapeutic programme for a child’s developmental needs (pre-school, primary school, secondary school and post-school) 4. Statutory assessment of special educational needs before the child begins formal education 5. Perform an annual review of progress and educational needs 6. Refer to social services departments and other agencies for respite and/or daily living support 7. Liaison with children’s disability teams 8. Refer for or provide appropriate psychological support and psychiatric intervention including psychopharmacology 9. Assess support required for vocational training and daily living in adult life 10. Provide support for parents and carers

TSC Behaviour Consensus Panel Members Michael Assel, Houston, TX, USA Patrick Bolton, London, UK Diane Chugani, Detroit, MI, USA Linda Creighton, TSAlliance, Silver Spring, MD, USA Petrus de Vries, Cambridge, UK Craig Elias, TSAlliance, Silver Spring, MD, USA David Franz, Cincinnatti, OH, USA Arni Hubbeling, Amsterdam, Netherlands Ayla Humphrey, Cambridge, UK Ann Hunt, Oxford, UK Bryan King, Dartmouth, NH, USA Celia Mastbaum, TSAlliance, NJ, USA Deborah McCartney, Cambridge, UK

Janet Medcalf, TSA, Bromsgrove, UK Johan Mulder, Rotterdam, Netherlands Penny Prather, Boston, MA, USA Khanum Ridler, Cambridge, UK Bonnie Rothberg, New Haven, CT, USA Paramala Santosh, London, UK Vicky Whittemore, TSAlliance, Silver Spring, MD, USA ■ Acknowledgements These consensus guidelines were compiled at the TSC Brain/Behaviour Workshop held January 10–12th 2003 and financially supported by the Tuberous Sclerosis Association and the Tuberous Sclerosis Alliance. We would also like to thank the Developmental Psychiatry Section, Department of Psychiatry, University of Cambridge for providing facilities for the meeting. We are grateful to Professor Tony Holland, Dr Hilary Lloyd, Professor Kieran Murphy and Dr Justin Williams for their helpful comments on this document.

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