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What is Tuberous Sclerosis Complex?

Tuberous sclerosis complex (TSC) is a multi-system genetic disorder caused by mutations in one of the tumor suppressor genes TSC1 or TSC2. It is characterized by abnormal growths in a wide range of organs including the skin, kidneys and central nervous system. In more than two-thirds of cases, diagnosis is made when an infant presents with seizures in the first year of life. In the brain, features include cortical tubers (CT), subependymal nodules (SEN), subependymal giant cell astrocytomas (SEGA) and widespread gray and white matter abnormalities. Intractable epilepsy is a major medical concern to doctors. Often, less attention is paid to the behavioral and neuropsychiatric problems also associated with TSC such as autism spectrum disorders (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and Anxiety Disorder.  Together with the intellectual and learning disabilities, behavioral and neuropsychiatric problems are often of greatest concern to families. Unfortunately, there is generally 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. 

Development of Guidelines for Cognitive and Behavioral Evaluation in TSC

Although clinical guidelines for physical aspects of TSC were established at a consensus conference in Annapolis, MD, in 1998, no specific guidelines were given on which behavioral and cognitive aspects to assess in TSC.  To address this situation, a consensus conference was convened in 2003 in Cambridge (UK) with the financial support and endorsement of the Tuberous Sclerosis Association (UK) and the Tuberous Sclerosis Alliance (USA). The aim was to produce clinical guidelines for cognitive and behavioral assessments of individuals with TSC using up-to-date evidence from research studies. The panel included parents of individuals with TSC, psychiatrists, neuropsychologists, psychologists, pediatric neurologists, and special education teachers. The research evidence and the consensus clinical guidelines were published in full in July 2005 (de Vries et al., 2005).  The information and Tables in this short summary are reproduced from the journal paper with the permission of the publishers.   

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 behavioral 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: (1) neurocognitive assessments to enable maximum support to be given for future cognitive development, and (2) behavioral assessments to diagnose problems that require psychiatric and/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 programs developed, and any clinical treatment offered should remain tailored to the individual, age and the local and national context.  

The guidelines recommend areas that are to be targeted in the context of TSC, but are not meant to imply limiting assessments only to those areas.  

The guidelines presented here are a consensus of expert opinion based on the best available evidence in the field. All peer-reviewed publications relating to cognition and behavior in TSC were used in the preparation of these guidelines and references are given in the full paper (de Vries et al, 2005). Unlike other disabling conditions such as Down's syndrome or Fragile-X syndrome, many aspects of cognition and behavior in TSC have received little systematic research so far and, in particular, areas such as language and academic skills lack full research. The guidelines are intended as advice to professionals who have individuals with TSC in their care, and as guidance to individuals, parents and caregivers about stages when assessments are to be sought. 

Summary of Cognitive and Behavioral Difficulties in TSC 

TSC is associated with a range of serious behavioral and cognitive difficulties in individuals with and without intellectual disability.  Table 1 summarizes these difficulties in TSC. The range of behavioral problems include sleep disturbance, aggressive behaviors, specific phobias, self-injury, temper tantrums, depressed mood and anxiety disorder. In particular, there is strong evidence for high rates of ADHD and ASD, and intellectual disability (IQ

Intellectual assessments in TSC divide individuals approximately into two groups. Around 55% function within the normal range of IQ (>80) while the rest have some degree of intellectual disability (ranging from mild to profound). About 30% of individuals with TSC have global intellectual ability in the profoundly impaired range (IQ

In some children with TSC, developmental outcome and progress may be correlated with the severity of their epilepsy and its control. Those with intellectual disability are more likely to have ASD or disruptive behaviors, but neither learning disability nor epilepsy are necessary or sufficient to explain the high rates of these behavioral disorders in individuals with TSC. There is also a high prevalence of significant language delay, even in those with normal intelligence. 

Among children and adults with TSC who have normal intelligence, there is increasing evidence of specific cognitive deficits in attentional and executive skills, even in individuals without behavioural signs of ADHD such as impulsivity or hyperactivity. People with problems in executive control processes may be inefficient and even inept in managing tasks that require planning, organization, monitoring and judgment. Memory skills may also be impaired in normally intelligent adults with TSC, particularly in retrieval of encoded memories. All these problems could also occur in people with moderate to profound intellectual disability who cannot be evaluated on the tests available at present. 

In the more moderately affected group, parents report significant difficulties in academic performance such as in reading, writing and arithmetic although these have not been researched in TSC. There were also reports that adults had difficulties in occupational functioning, such as in establishing a career or vocation, and in the ability to “multi-task” in the workplace. These problems can lead to very high rates of low self-esteem and to a high burden of care and stress on families.  In some areas, difficulties are reported in obtaining appropriate services from statutory and non-statutory agencies such as educational authorities, social services departments, or health care providers or insurance companies due to the lack of understanding of the problems specific to TSC that have been identified by research. 

Rationale for the Guidelines 

Research has shown that TSC is a brain disorder with a high prevalence of cognitive and behavioral difficulties. Some of these difficulties, such as ASD or ADHD, will have clear social consequences and require intensive help and support. Others, such as attention or memory deficits, could easily be missed in a normally intelligent child, and quite severe educational problems can follow. 

Therefore, it is important to know if a child or adult with TSC has such disabilities or not. If a child is routinely checked for problems known to be associated with TSC, backed up by accepted assessment tests, this would then enable a child to be offered, from the beginning, an individual remedial program if it were required. It can never be good practice to put such children or adults, without assessment, into a situation where they fail, and only after failure assess them and offer help. Routine checks would minimize the risk of added complications developing, thus avoiding not only expensive and protracted interventions but also the emotional trauma induced in a child or adult who fails. 

Consensus Recommendations

Panel Recommendation I: Perform regular assessment of cognitive development and behavior to identify and treat emerging difficulties and to establish a baseline for evaluating any later changes. 

Assessments should be tailored to the presentation of problems shown by each individual and are to be performed at the recommended ages, as shown in Table 2.  The pre-school assessments are to be routinely done to identify developmental and behavioral impairments that otherwise can be difficult to identify in young children and to establish a baseline measure against which any future changes may be compared. Extra assessments may be necessary if new clinical concerns emerge as the child develops. Evaluations should use neuropsychological and behavioral tools appropriate to the developmental level of the individual so that these results can be interpreted against those of the population at large. 

It may not be necessary or appropriate to assess for every area of difficulty in every individual at every age. Global cognitive, motor and language development are very important in infants and young children, but emotional problems and skills needed for independent living are more relevant to adolescents and adults. Assessment of the various areas will involve different professionals such as developmental or community pediatricians, speech and language therapists, clinical or educational psychologists, psychiatrists in child, adolescent, and adult and learning disability services. These cognitive and behavioral profiles will be useful to the local multidisciplinary care team in planning the services needed by the person with TSC and will enable a review of longitudinal progress and response to treatment and support.   

Panel Recommendation II: Perform a comprehensive assessment when there are changes in cognitive development or behavior to identify and treat the underlying causes of neurobehavioral change. 

Changes in behavior (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 or vision) should always be assessed and appropriately investigated. Regression and deterioration of functional abilities are not characteristics of TSC, 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, 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, producing increased pressure on the brain. In such circumstances there may be an associated deterioration in behavior and intellectual ability or, potentially, the emergence of specific cognitive impairments. 

Investigations of these changes should therefore include a comprehensive physical and neurological review, functional analysis of behavior, neuropsychological evaluation, and appropriate special investigations such as biochemical profile, EEG and MRI. 

Consensus Panel Guidelines 

The consensus guidelines for routine cognitive and behavioral assessments recommend assessments at set stages and are presented in Table 2. For each assessment stage, the age range for the assessment is given and the general purpose of assessments is outlined. Specific concerns to pay attention to in TSC are also listed for each stage. Even if an early assessment is within normal limits, reassessment should be performed when the individual is moving 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 Tests 

There is a wide range of neuropsychological tests in general use in different countries, with some that are routine in pre-school or school settings and others that are more specialized tools derived from research studies. Some of the tests most often used in the U.S.A. are shown in Table 3, but those used will depend on local resources and preferences. However, the areas of potential difficulty will not vary, and it is important that these areas are assessed appropriately.  

The clinical diagnosis of psychiatric disorders should be made according to established international diagnostic criteria such as ICD-10 and DSM-IV. A range of supplemental tools such as interviewer-based schedules, observational schedules, and behavioral rating scales are available to aid the diagnostic process by clinicians. 

Post-Assessment Interventions 

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 specialties and multi-agency involvement. Table 4 lists a range of possible outcomes of neurobehavioral assessments.  

TSC Behavior Consensus Panel Members

These consensus guidelines were compiled at the TSC Brain/Behavior Workshop held January 10-12, 2003, in Cambridge, UK, and financially supported by the Tuberous Sclerosis Association (UK) and the Tuberous Sclerosis Alliance (USA). 

Michael Assel, Ph.D., Houston, TX, USA
Patrick Bolton, M.D., Ph.D., London, UK
Diane Chugani, Ph.D., Detroit, MI, USA
Linda Creighton, M.S.W., TS Alliance, MD, USA
Petrus de Vries, M.D., Ph.D., Cambridge, UK
Craig Elias, TS Alliance, MD, USA
David Neal Franz, M.D., Cincinnati, OH, USA
Arni Hubbeling, M.D., Amsterdam, Netherlands
Ayla Humphrey, Ph.D., Cambridge, UK
Ann Hunt, Oxford, UK
Bryan King, M.D., Dartmouth, NH, USA
Celia Mastbaum, TS Alliance, NJ, USA
Deborah McCartney, Cambridge, UK
Janet Medcalf, TSA, Bromsgrove, UK
Johan Mulder, Ph.D., Rotterdam, Netherlands
Penny Prather, Ph.D., Boston, MA, USA
Khanum Ridler, Ph.D., Cambridge, UK
Bonnie Gould Rothberg, M.D., New Haven, CT, USA
Paramala Santosh, M.D., London, UK
Vicky Whittemore, Ph.D., TS Alliance, MD, USA 


de Vries P, Humphrey A, McCartney D, Prather P,  Bolton P, Hunt A, TSC Behaviour Consensus Panel (2005) Consensus clinical guidelines for the assessment of cognitive and behavioural problems in Tuberous Sclerosis. Eur Child Adolesc Psychiatry 14(4):183-90

Prather P, de Vries, PJ (2004) Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol 19(9):666-74

Summary prepared by Ann Hunt, Director of Research (Retired), Tuberous Sclerosis Association, U.K.  Reviewed and updated by Petrus de Vries, MBChB, MRCPsych, PhD, March 2011.

**Tuberous Sclerosis Alliance Information Sheets are intended to provide basic information about TSC. They are not intended to, nor do they, constitute medical or other advice. Readers are warned not to take any action with regard to medical treatment without first consulting a physician.  The TS Alliance does not promote or recommend any treatment, therapy, institution or health care plan.

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