International consensus recommendations for the identification and treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND)

de Vries et al. Journal of Neurodevelopmental Disorders (2023) 15:32 https://doi.org/10.1186/s11689-023-09500-1 Journal of Neurodevelopmental Disorders Open Access RESEARCH International consensus recommendations for the identification and treatment of tuberous sclerosis complex‑associated neuropsychiatric disorders (TAND) Petrus J. de Vries1* , Tosca‑Marie Heunis2 , Stephanie Vanclooster2, Nola Chambers1 , Stacey Bissell3, Anna W. Byars4,5 , Jennifer Flinn6, Tanjala T. Gipson7,8 , Agnies M. van Eeghen9,10 , Robert Waltereit11 , Jamie K. Capal12 , Sebastián Cukier13 , Peter E. Davis14, Catherine Smith15, J. Chris Kingswood16,17 , Eva Schoeters18,19, Shoba Srivastava1,20, Megumi Takei21, Sugnet Gardner‑Lubbe22 , Aubrey J. Kumm1 , Darcy A. Krueger4,5 , Mustafa Sahin14,23 , Liesbeth De Waele24,25   and Anna C. Jansen2,26,27    Abstract Background Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically underidentified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific. Methods The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treat‑ ment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own system‑ atic procedure for evidence review and consensus-building to generate evidence-informed consensus recommenda‑ tions of relevance to the global TSC community. Results At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to “screen” for TAND at least annually, to “act” using appropriate next steps for evaluation and treatment, and to “repeat” the process to ensure early iden‑ tification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families. *Correspondence: Petrus J. de Vries Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom‑ mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. de Vries et al. Journal of Neurodevelopmental Disorders (2023) 15:32 Page 2 of 20 Conclusions The consensus recommendations should provide a systematic framework to approach the identifica‑ tion and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a “TAND toolkit” of “what to seek” and “what to do” when difficulties are identified in TAND clusters. Keywords Tuberous sclerosis complex, TAND, Rare genetic disorders, Consensus recommendations, Neurodevelopmental disability, Mental health, Education Background Tuberous sclerosis complex (TSC) is a rare genetic disorder associated with mutations in the TSC1 or TSC2 genes, a wide range of physical manifestations, and a highly heterogeneous clinical presentation [1, 2]. TSC is also associated with a broad range of behavioral, psychiatric, intellectual, academic, neuropsychological, scholastic, and psychosocial difficulties [3–5]. Until the 1990s, diagnosis, monitoring, and treatment of TSC tended to be inconsistent and highly variable across the globe. In an attempt to standardize the diagnosis of TSC, a consensus conference was convened in 1998. The meeting led to a simplified and revised set of diagnostic criteria for TSC [6] and was accompanied by recommendations for diagnostic evaluation [7]. The 1998 and 1999 consensus publications provided a structured approach to the physical manifestations of TSC. Given the emerging awareness of the neuropsychiatric manifestations of TSC at the time, the consensus panel also aimed to include information about neuropsychiatric manifestations of TSC, albeit in a limited manner. The recommendations made in relation to “neurodevelopmental testing” suggested “thorough age-appropriate screening for behavioral and neurodevelopmental dysfunction” at the time of diagnosis, and reassessment at school entry. “Periodic” retesting was recommended for older children with “previous test abnormalities,” for those with “abnormal cognitive function or behavior,” and when there was a significant change in behavior. No evaluations were recommended for newly diagnosed adults who appeared not to have any difficulties, and no further evaluations were recommended of those who appeared “normal” or had “stable disabilities” [7]. To provide a more systematic and proactive set of recommendations for the assessment of “cognitive and behavioral problems” in TSC, a meeting was convened in Cambridge, UK, in 2003. The consensus panel, consisting of 20 clinicians, researchers, and family representatives from the USA, UK, and the Netherlands, made two main recommendations [5]. First, to perform a comprehensive (...truncated)