Original ArticleTuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist
Introduction
Tuberous sclerosis complex (TSC) is a multisystem disorder associated with multiorgan involvement, including the brain, kidneys, heart, eyes, and lung.1, 2 The disorder has a birth incidence of approximately 1:6000 and is seen at similar prevalence rates around the globe.3 In approximately 85% of cases, a mutation is identified in the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p13.3) genes. The TSC1-TSC2 protein complex acts as an upstream regulator of mammalian target of rapamycin (mTOR).1, 2, 4 Disruption of this regulatory role leads to mTOR overactivation and to dysregulated growth control, thus explaining the fundamental pathophysiological mechanism of the disorder.1, 2, 4 In recent years, molecularly targeted treatments using mTOR inhibitors have been introduced for some of the specific organ systems involved, such as subependymal giant cell astrocytomas of the brain and angiomyolipomas of the kidney.5, 6, 7, 8
Given the significant progress in understanding the pathophysiology of TSC over the last 2 decades, the International Consensus Conference was convened in 2012 to revise the diagnostic criteria and to refine the assessment, surveillance, and treatment guidelines for TSC. Revised diagnostic and surveillance guidelines were published in 2013.9, 10
Apart from the range of physical manifestations of TSC, individuals with the disorder may also be affected by a wide array of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties.11, 12 In both clinical practice and scientific publications, these multiple levels of difficulties have been referred to by many different terms, including “neurocognitive issues,” “neurobehavioral difficulties,” “learning issues,” “mental health issues,” “neuropsychiatric disorders,” “cognitive and behavioral difficulties,” and so on. Most individuals who live with TSC will experience some of these difficulties in their lifetime. Similar to the physical manifestations of TSC, there is also growing evidence that specific elements of neuropsychiatric disorders in TSC may be directly attributable to dysregulation of mTOR signaling and that mTOR inhibitors might therefore also become molecularly targeted treatments for some of these aspects of TSC.11, 12, 13, 14, 15
In 2003 an international consensus panel was convened to develop guidelines for the assessment of “cognitive and behavioral problems” in individuals with TSC. The recommendations were published in 2005.16 The panel made two main recommendations. The first was to perform regular assessment of cognitive development and behavior in all children and adolescents with TSC to establish a baseline for evaluating changes in developmental trajectories and to identify and treat emerging difficulties. The second was to perform a comprehensive assessment (particularly a comprehensive physical evaluation) in response to sudden or unexpected changes in cognitive development or behavior to identify and treat the underlying cause of neurobehavioral change.16
In a survey of members of the UK Tuberous Sclerosis Association 5 years after the publication of these guidelines, only 18% of all families had ever received any of the evaluations or treatments recommended in the 2005 guidelines. Given that more than 90% of all individuals with TSC are likely to have some of these challenges,17 the “treatment gap” (the difference between clinical need and services provided) was therefore in excess of 70%. This finding is in keeping with global findings of treatment gaps in mental health where it is not uncommon for 70%-80% of individuals who have mental disorders not to receive any treatment.18
Given the multidimensional nature of these difficulties associated with TSC across multiple levels, the clinical and scientific confusion about different terminologies used, and the significant treatment gaps identified, the Neuropsychiatry Panel at the 2012 International Consensus Conference were keen to identify a strategy that would increase awareness of the need to screen for these difficulties, simplify and clarify the terminology used around behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial aspects of TSC, and develop a simple tool to facilitate clinical teams and families to screen for these challenges to identify areas that require more in-depth evaluation or treatment.
The Neuropsychiatry Panel commented that the “treatment gaps” observed in TSC were similar to those observed in the human immunodeficiency virus (HIV) community, where there used to be an overemphasis on physical treatment of HIV-positive individuals without consideration of the major neurocognitive and neuropsychiatric features of HIV.19 The HIV community introduced the concept of HAND (HIV-associated neurocognitive disorders) as a strategy to raise awareness of such concerns. Inspired by the HIV example, the TSC Neuropsychiatry Panel therefore decided to coin the term TAND (TSC-associated neuropsychiatric disorders) and recommended that all individuals with TSC should be screened for TAND at least once per year. To facilitate the process, a TAND Checklist was developed. Pilot validation of the TAND Checklist was performed and is presented elsewhere.17
Here, we outline the conceptualization of the multidimensional nature of TAND and present a TAND Checklist for clinical use.
Section snippets
The multiple dimensions of TAND
Infants, children, adolescents, and adults with TSC may present with a varied and variable range of challenges across multiple “levels or dimensions.”11, 20
The concept of TAND
TAND aims to bring together under a single term the multiple levels of involvement that relate to the neurobiological, psychological, and social aspects of TSC. The term was coined to generate a unifying rubric to be used as a “short-hand” to capture all the possible functional manifestations, complications, and consequences of TSC that relate to behavior, mental health or psychiatric disorders, neurodevelopment, intellectual, academic, neuropsychologic, and psychosocial abilities.
The term is
The TAND Checklist
Given the attempt of the Neuropsychiatry Panel to unify terminology and delineate a shared language to describe the multiple dimensions of TAND, we agreed to develop a short, freely accessible TAND Checklist to aid health-care professionals and families in screening for TAND.
The purpose of the TAND Checklist is to act as a memory aid or a basic structure to guide a conversation between the clinician and family or individual with TSC. The conversation that flows from the TAND Checklist should
The structure of the TAND Checklist
The overall structure of the TAND Checklist is outlined in the Table. Conceptually, the 12 items (referred to as questions) follow the levels of investigation outlined previously and require simple YES or NO responses to most questions.
The introductory items (questions 1 and 2) aim to get a general sense of developmental milestones and of the current level of functioning of the individual about whom the conversation is taking place. These items were placed first to ensure that the interviewer
Pilot validation of the TAND Checklist
The pilot validation of the TAND Checklist, using a mixed-method approach, is presented in detail elsewhere.17 In phase I of the pilot validation, expert professionals (n = 20) and expert parents or caregivers (n = 42) from 28 countries were asked to comment on the clarity, comprehensiveness, ease of use, and likely use of the TAND Checklist. Results suggested that the TAND Checklist was clear, comprehensive, and easy to use. Participants generally felt that clinical teams would use it, but
How does the TAND Checklist fit into the 2012 International TSC consensus recommendations for the assessment and management of TAND?
As outlined elsewhere,10 the Neuropsychiatry Panel recommended screening for TAND at least annually. We suggest that the TAND Checklist might be a useful guide to perform this task. Any areas of concern identified should lead to appropriate next-step evaluations or treatment.
In addition, we also recommended that comprehensive formal assessments for TAND should be performed at key developmental time points. These include infancy (age 0-3), pre-school years (age 3-6), primary school years (age
Next steps with the TAND Checklist
The TAND Checklist is provided here in English. Next steps will include working with local organizations in various countries to prepare translations of the TAND Checklist. Translations will be done using a standardized procedure including translation, blind back-translation, and authorization by the authors of the TAND Checklist. The TAND Checklist was developed to be freely available to increase the likelihood of its uptake in real-life settings.
Further studies using the current version of
Conclusion
Here the Neuropsychiatry Panel of the 2012 International Consensus Conference for TSC presented the rationale for and conceptualization of a new term, TAND. The overall purpose of this new term was to define a unifying construct to describe the multidimensional biopsychosocial manifestations seen in TSC. We hope that this unified term will raise awareness of the importance of TAND and of the major burden of disease associated with it, provide a shared language to describe and evaluate the
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