Table 1 Historical developments in TAND research

1880

TSC defined as a disorder of the brain [19]

1908

Description of the ‘triad of impairment’ which included seizures/epilepsy, intellectual disability and facial angiofibromas [20]

1911

The term ‘epiloia’ coined to describe epilepsy combined with ‘anoia’ (intellectual disability) in individuals with TSC [21]

1932

First descriptions of behaviours suggestive of autism, behavioural manifestations and different intellectual levels in individuals with TSC [22]

1967

First set of diagnostic criteria for TSC—not including any TAND manifestations or reference to seizures/epilepsy [23]

1983

First systematic research on behavioural aspects of TSC [24,25,26]

1987

Exploration of infantile spasms and its relationship with behavioural manifestations in TSC (e.g. autism, hyperkinetic behaviour, psychosis and aggression) [27]

1991

Consideration of neuropsychological deficits in TSC, in relation to memory, attention and executive functions [29]

1993

Further exploration of links between TSC and varied behavioural problems and identification of risk markers of behavioural manifestations [28]

1998

First International TSC Consensus Conference to develop revised diagnostic criteria and clinical management guidelines with little consideration of TAND [32, 33]

2005

TSC Behaviour Consensus Panel publish clinical guidelines for the assessment of cognitive and behavioural problems in TSC: recommendations of comprehensive assessment during all key developmental phases to identify emerging TAND and urgent assessment in case of sudden or unexpected change [36]

2007

Molecular hypothesis for the causes of TAND: the GRIPP hypothesis proposed that there is a direct molecular pathway from gene disruption to psychopathologies and that molecularly targeted treatments may reverse these deficits [42]

2008

First animal models of TSC2+/- showing reversal of learning deficits in response to mTORi [45]

2011

First human findings to show improvement in memory and executive deficits in humans with TSC after mTORi in an open-label trial [44]

2012

Second International TSC Consensus Conference to revise diagnostic criteria, as well as surveillance and treatment guidelines for TSC [8]

The term ‘TAND’ was coined, and the recommendation was made to screen for TAND on an annual basis [9].

2012

Establishment of the TuberOus SClerosis registry to increase Awareness (TOSCA) consortium: the first large-scale international collaboration to study physical and TAND manifestations [49,50,51]

2015

Pilot validation and publication of the TAND Checklist [14, 17] with subsequent translation and authorisation in 19 languages (http://www.tandconsortium.org)

2016

Inclusion of TAND in Research Strategic Plan for TSC [52]

2017

First publication of randomised controlled trial findings on TAND from everolimus and sirolimus clinical trials [47]

2018

First description of natural TAND clusters [53]

2019

Launch of the TANDem project and establishment of the TAND consortium (http://www.tandconsortium.org)

2020

Replication of natural TAND clusters [54]

2021

Updated TSC Diagnostic Criteria and Surveillance and Management Recommendations including consensus guidelines for the identification and treatment of TAND [12]