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Background Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research. Methods The study was conducted in accordance with stages outlined within the Arksey and O’Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined. Results Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low–middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder–like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%). Conclusions Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified.
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Vancloosteretal.
Journal of Neurodevelopmental Disorders (2022) 14:13
https://doi.org/10.1186/s11689-022-09423-3
REVIEW
The research landscape oftuberous sclerosis
complex–associated neuropsychiatric disorders
(TAND)—a comprehensive scoping review
Stephanie Vanclooster1†, Stacey Bissell2†, Agnies M. van Eeghen3,4, Nola Chambers5, Liesbeth De Waele6,7,
Anna W. Byars8, Jamie K. Capal9, Sebastián Cukier10, Peter Davis11 , Jennifer Flinn12, Sugnet Gardner‑Lubbe13,
Tanjala Gipson14,15, Tosca‑Marie Heunis1, Dena Hook16, J. Christopher Kingswood17,18, Darcy A. Krueger19,20,
Aubrey J. Kumm5, Mustafa Sahin21 , Eva Schoeters22, Catherine Smith16, Shoba Srivastava5,23, Megumi Takei24,
Robert Waltereit25, Anna C. Jansen1,26 and Petrus J. de Vries5*
Abstract
Background: Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) is an umbrella term
for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC.
Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under‑
assessed, under‑treated and under‑researched. We performed a comprehensive scoping review of all TAND research
to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND
research.
Methods: The study was conducted in accordance with stages outlined within the Arksey and O’Malley scoping
review framework. Ten research questions relating to study characteristics, research design and research content of
TAND levels and clusters were examined.
Results: Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal stud‑
ies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in
2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults
(16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA
(89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low–middle income countries
(LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant
variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non‑pharmacological,
and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the
autism spectrum disorder–like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the
least (53/200; 27%).
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
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licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco
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Open Access
*Correspondence: Petrus.devries@uct.ac.za
Stephanie Vanclooster and Stacey Bissell contributed equally to this
work.
5 Division of Child & Adolescent Psychiatry, Centre for Autism Research
in Africa (CARA), University of Cape Town, Cape Town, South Africa
Full list of author information is available at the end of the article
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Page 2 of 23
Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
Background
Tuberous sclerosis complex (TSC) is an autosomal domi-
nant genetic disorder characterised by multisystem
involvement [1, 2]. e most common physical manifes-
tations include benign tumours in the central nervous
system, skin, kidneys, heart and lungs and high rates of
epilepsy [2, 3]. TSC is caused by a pathogenic variant in
one of two genes, TSC1 or TSC2 [4, 5]. e protein prod-
ucts of TSC form an intracellular complex to regulate
mammalian/mechanistic target of rapamycin (mTOR)
signalling [1, 6]. Dysregulation of mTOR signalling leads
to overactivated mTOR as the core molecular mechanism
of the disorder [79]. Among individuals with TSC, there
is significant phenotypic variability in the number and
severity of symptoms [3, 8]. Some physical characteris-
tics of the disorder have an age-related expression pat-
tern with cardiac rhabdomyomas, subependymal nodules
and cortical tubers often emerging prenatally or in early
infancy, and renal angiomyolipomas and lymphangiolei-
omyomatosis presenting more often in adolescence and
adulthood [10, 11]. Evidence-based management and
co-ordination of care across medical specialists is crucial
throughout the lifespan to reduce morbidity and mortal-
ity in TSC [8, 12].
In addition to the physical manifestations of TSC, the
disorder is also associated with a wide range of behav-
ioural, psychiatric, intellectual, academic, neuropsy-
chological and psychosocial difficulties [1, 1315].
Collectively, these are referred to as TSC-associated
neuropsychiatric disorders or ‘TAND’, a term coined in
2012 [13]. Approximately 90% of people with TSC evi-
dence TAND manifestations at some point in their lives,
and TAND has been identified by families as the greatest
clinical burden of the disorder [13, 1618]. Similar to the
physical manifestations, TAND also has an age-related
expression with some difficulties or disorders more prev-
alent in infancy or early childhood (e.g. impulsivity and
overactivity), and others emerging or presenting later
across the lifespan (e.g. anxiety and depressed mood)
[1316, 19]. Although a genotype–intellectual pheno-
type relationship is well delineated in TSC, with a more
severe phenotype associated with the TSC2 variant, a
TSC1 TSC2 differentiation is overly simplistic in relation
to TAND. ere is a complex multi-directional associa-
tion between the physical and neuropsychiatric aspects
of TAND. As discussed in more detail below, seizure
severity, intellectual ability, developmental outcomes and
autism characteristics are interrelated [20]. ere is also
a humanistic impact to educational, social, psychological
and quality of life outcomes as a result of physical health
determinants, including epilepsy, medication side effects
and pain [21].
A brief history ofTAND research
From a historical perspective, the association between
TSC and TAND has been noted from very early on in
the narrative of TSC research. On the first description of
‘sclérose tubéreuse des circonvolutions cérébrales’ (tuber-
ous sclerosis of the cerebral cortex), TSC was conceptual-
ised as a disorder of the brain [22]. Only when Vogt [23]
described the ‘triad of impairment’ (seizures/epilepsy,
intellectual disability and angiofibromas of the skin) did
TSC become a disorder of multisystem involvement.
Early descriptive studies by Sherlock [24] and Critch-
ley and Earl [25] in particular, showed clear associations
between TSC and a range of behaviours that would now
be associated with psychopathologies such as autism,
attention deficit hyperactivity disorder (ADHD) or psy-
chotic disorders. Early diagnostic criteria, however, only
described the physical manifestations of TSC [26]. e
pioneer of systematic research on the behavioural aspects
of TSC was the UK scientist, parent and co-founder of
the UK Tuberous Sclerosis Association (TSA), Ann Hunt,
who in 1983 published a set of papers on behaviours and
family perspectives [2729], and later published research
exploring behavioural ‘risk markers’ [30, 31]. Jambaqué
etal. in France [32] described the first systematic evalu-
ation of neuropsychological profiles in TSC and showed
that over and above intellectual disability, many people
with TSC (including those with normal intellectual abil-
ity) had specific neuropsychological deficits in memory,
attention, language and executive skills.
e link between physical and neuropsychiatric aspects
of TSC became more established with improvements
in neuroimaging techniques. Research in the mid–late
1990s explored correlations between structural brain
Conclusions: Despite the recent increase in TAND research, studies that represent participants across the lifespan,
LMIC research sites and non‑pharmacological interventions were identified as future priorities. The quality of cohort
studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In
human studies, the academic level in particular warrants further investigation. Remote technologies could help to
address many of the TAND knowledge gaps identified.
Keywords: Tuberous sclerosis complex, Scoping review, TSC‑associated neuropsychiatric disorders, Autism,
Behaviour, Psychiatric, Intellectual, Scholastic, Neuropsychological, Psychosocial
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Page 3 of 23
Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
abnormalities such as cortical tubers and a range of
TAND-related manifestations, most notably autism
and intellectual disability (e.g. [33, 34]). e first set of
consensus diagnostic criteria for TSC in 1998 [35, 36]
acknowledged the presence of neurodevelopmental
concerns and recommended ‘thorough age-appropriate
screening for behavioural and neurodevelopmental dys-
function’ at diagnosis and re-evaluation ‘as indicated’.
TAND research in the 2000s continued to describe the
range of TAND manifestations and started to stratify
and correlate these in relation to intellectual ability level,
and/or seizures (e.g. [37, 38]). As research broadened
across age groups, different manifestations of behaviour
in TSC were found to be linked to different stages across
the lifespan. is lifespan perspective and advocacy
from parent organisations such as the TSA for proactive
assessment of TAND, led to the generation of consensus
clinical guidelines for the assessment of behavioural and
cognitive problems in TSC [39]. ese guidelines recom-
mended comprehensive evaluation at key developmen-
tal timepoints (e.g. infancy, pre-school, primary years,
adolescence, early adulthood) and urgent assessment in
response to sudden and unexpected changes in behav-
iour or cognition. Later in that decade, specific profiles
of behaviour were more extensively explored along with
potential ‘risk markers’ for such behaviours [4042].
After the identification of the role of the TSC1 and
TSC2 genes in intracellular signalling in the mTOR sig-
nalling pathway [43, 44], TAND research started to shift
focus to the potential role of molecular pathways to psy-
chopathology. For example, de Vries and Howe published
the ‘global regulator and integrator of a range of physi-
ological processes’ (GRIPP) hypothesis [45] stating that
structural and electrophysiological features of TSC are
neither necessary nor sufficient to explain TAND mani-
festations and proposed that mTOR dysregulation may
represent a direct pathway to TAND. erefore, TAND
manifestations may be reversed or improved by mTOR
inhibitors (mTORi) or other molecularly targeted treat-
ments [16, 45]. TAND research since then has examined
animal models in relation to mTORi, and phase I and II
clinical trials of mTORi in humans emerged [46]. In spite
of initial encouraging findings of improvement in specific
TAND manifestations in animal models and early-phase
human trials [4749], more recent results have been
mixed [50, 51].
At the International TSC Consensus Conference in
2012, the Neuropsychiatry Panel recognised that the
2005 guidelines [39] were rarely followed and that the
majority of neuropsychiatric manifestations in TSC were
not identified or treated [8, 13].
Here, the emphasis on psychosocial aspects of TSC
and ‘burden of illness’ gained precedence. e financial,
humanistic, and quality of life impacts to individuals,
caregivers and families were noted, including healthcare
costs, caregiver stress and school absenteeism [52, 53].
Individuals and caregivers reported stressors in relation
to both physical characteristics (e.g. skin lesions, tumour
burden, epilepsy) and TAND (e.g. poor sleep, stigma,
depression, social isolation [54]). Physical characteris-
tics such as active seizure status, adverse medication
side effects, and TSC-specific severity of manifestations
have been found to predict health-related quality of life
and TAND outcomes (e.g. social involvement, emotional
well-being, cognitive functioning [55]). Caregivers in
particular noted concerns regarding transition into adult
services and a lack of multidisciplinary involvement and
specialist care [54].
ere was therefore a clear ‘identification and treat-
ment gap’ of these manifestations [14]. In addition, the
panel noted that there was significant confusion in the
international literature about the many different ‘levels’
of neuropsychiatric manifestations, with differing ter-
minology used across the globe. As a result, the panel
coined the term ‘TAND’ for two reasons: firstly, to cre-
ate a simple ‘umbrella’ term to capture the wide range
of neuropsychiatric manifestations associated with TSC
and, secondly, to provide a ‘shared language’ to define the
different levels of TAND [13]. Consequently, TAND was
included as a core component of an international patient
registry [19, 56, 57] and was outlined as a recommenda-
tion for future research as of 2016 [58]. is timeline of
TAND research to date is summarised in Table1.
Table2 presents a summary of the different levels of
TAND as defined by the Neuropsychiatry Panel [8].
Given the possible changes over time in an individual’s
TAND profile, it was recommended that all individuals
with TSC should be screened for TAND at least annually
[8]. e TAND Checklist was developed to guide health-
care practitioners in screening across the different levels
of neuropsychiatric functioning [13, 17].
Apart from the ‘assessment and treatment gap’
described in TAND, it was also clear that the wide
range of TAND manifestations across the lifespan pre-
sented an almost ‘overwhelming uniqueness’ of TAND
profiles resulting in a ‘treatment paralysis’, as described
by Leclezio and de Vries [14]. e authors used a data-
driven strategy to identify natural clusters of TAND man-
ifestations with a view towards creating a smaller number
of typical TAND profiles that could guide identification
and intervention for TAND [61]. Following feasibil-
ity [61] and replication [62], findings from a large-scale
study of 453 participants revealed seven natural TAND
clusters: a scholastic cluster, a neuropsychological cluster,
a dysregulated behaviour cluster, an overactive/impul-
sive cluster, an eat/sleep cluster, a mood/anxiety cluster
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
and an autism spectrum disorder–like cluster [63]. e
clusters represent typically occurring groupings of the
specific manifestations associated with the six different
levels of TAND, as shown in Table 2. Table3 outlines
these seven natural TAND clusters and their items.
It is important to acknowledge the conceptual distinc-
tion between TAND levels and clusters. TAND levels
distinguish between six discrete aspects relating to the
neuropsychiatric characteristics of TSC. is is a simple
and heterogeneous approach, which is pragmatic within
a clinical context to ensure each level is explored within
the TAND Checklist. Levels ‘categorise’ discrete TAND
manifestations, but it is important to note that each level
does not occur in isolation. Clusters by comparison con-
sider the overlap and co-occurrence of items beyond
levels, in reference to an individual’s TAND profile or
‘signature’. Clusters ‘group’ naturally co-occurring TAND
manifestations based on large-scale data modelling [63],
with a view towards more personalised identification and
treatment.
Describing theresearch landscape ofTAND
e last three decades have seen progress in the field
of TAND research. However, as previously outlined,
TAND is a broad and complex construct. Despite the
increased interest and output in TAND, there has
been no comprehensive synthesis of TAND findings to
guide clinical decision making or directions for future
research. Table4 outlines the key unanswered ‘big pic-
ture’ questions in the field. ese research questions
are presented in chronological order of their relative
impact to the TSC research field in line with the back-
ground history of TAND research. Both TAND levels
and clusters are clinically relevant; however, TAND
levels are comparatively more established in accord-
ance with TAND Checklist structure and content [13].
Table 1 Historical developments in TAND research
GRIPP Global regulator and integrator of a range of physiological processes, mTORi Mechanistic target of rapamycin inhibitors, TANDem ‘Empowering families through
technology: a mobile-health project to reduce the TAND identication and treatment gap’
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 [2426]
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 [4951]
2015 Pilot validation and publication of the TAND Checklist [14, 17] with subsequent translation and authorisation in 19 languages (http:// www. tandc
onsor tium. 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. tandc onsor tium. 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]
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
Exploring TAND levels within a scoping review context
also enables a consideration of important psychosocial
aspects of TSC that are not fully encapsulated within
the TAND cluster framework. erefore, research
questions are mainly addressed in relation to TAND
levels, with a brief exploration of clusters in the last
question. e current review set out to identify and
evaluate all TAND research to date, with the aims of:
(a) describing the research landscape of TAND and (b)
finding knowledge gaps in TAND research that could
Table 2 The different levels of TAND
DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [59], ICD-11 International Classication of Diseases and Related Health Problems, Eleventh
Edition [60]
Level Name Description Examples
Level 1 Behavioural level This level includes all observed behaviours. The behav‑
ioural level is typically evaluated through direct obser‑
vation or through a range of rating scale measures.
Aggression, anxiety, depressed mood, overactivity,
impulsivity, poor eye contact, repetitive and ritualistic
behaviours, sleep problems
Level 2 Psychiatric level This level is defined by psychiatric diagnostic classifica‑
tion systems such as DSM‑5 or ICD‑11. At this level, the
clinician determines whether behaviours observed at
level 1 meet criteria for specific psychiatric disorders.
ADHD, autism, anxiety disorder, depressive disorder
Level 3 Intellectual level This level measures intellectual ability as defined by
standardised IQ‑type measures. Intellectual ability within the normal, mild, moderate,
severe or profound range.
Level 4 Academic level This level refers to specific learning disorders (as
defined in DSM‑5) associated with scholastic perfor‑
mance.
Reading, writing, spelling, or mathematics disorder.
Level 5 Neuropsychological level This level examines specific brain‑referenced systems
through the use of standardised neuropsychological
instruments.
Selective, sustained or dual‑tasking attention deficits;
unilateral neglect; immediate recall memory deficits;
spatial working memory deficits; visuo‑spatial deficits;
executive deficits
Level 6 Psychosocial level This level explores the psychological and social impact
of TSC in terms of self, family and community relation‑
ships.
Low self‑esteem, low self‑efficacy, high family stress,
parental relationship difficulties, community stigma and
isolation
Table 3 The seven natural TAND clusters and their items
TAND clusters TAND items
1. Scholastic Reading, writing, spelling, mathematics
2. Neuropsychological Memory, disorientation, attention deficits (behavioural and neuropsychological), visuo‑spatial deficits,
dual‑task deficits, executive function deficits
3. Dysregulated behaviour Aggressive outbursts, temper tantrums, self‑injury
4. Overactive/impulsive Overactivity, impulsivity, restlessness
5. Eat/sleep Eating difficulties, sleep difficulties
6. Mood/anxiety Anxiety, depressed mood, extreme shyness, mood swings
7. Autism spectrum disorder–like Inflexibility, unusual language, delayed language, repetitive behaviours, poor eye contact, peer difficulties
Table 4 Key scoping review questions
1. How much TAND research has been done over the years?
2. Where has TAND research been done in the world?
3. Which TSC age groups have been investigated?
4. What is the overall quality of existing TAND research?
5. Which TAND levels have been investigated?
6. Which research methods and research measures have been used to investigate TAND?
7. How much quantitative and qualitative TAND research has been conducted?
8. How many intervention studies have been conducted?
9. Have remote technologies been utilised to study TAND?
10. Which TAND clusters have been studied?
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
inform priority setting and recommendations for future
TAND research.
Methods
Scoping review methodology
To investigate these two key aims and directly address
the ten research questions outlined in Table4, a scoping
review methodology was adopted. A key component of
a scoping review is ‘mapping’ [64]: synthesising what is
currently known about a research topic, identifying gaps
in current understanding and conceptually analysing the
available literature to inform the focus of future research
[65, 66]. Unlike systematic reviews, studies in a scoping
review are not excluded on the basis of quality, although
it is generally recommended that methodological quality
of studies should be assessed to aid in the interpretation
of scoping review results [64]. e five stages of the Ark-
sey and O’Malley framework [67] for conducting a scop-
ing review were followed (outlining research questions,
study identification, study selection, data charting, analy-
sis and interpretation). In addition, a quality assessment
of studies was also conducted.
Study identication
A systematic search of the following databases was con-
ducted by the co-first author (SV) between February and
March 2020: CINAHL, Cochrane Library, Embase, ERIC,
MEDLINE, PsycARTICLES, PubMed, Sage Journals, Sci-
ence Direct, Scopus (Elsevier), Springer Link and Web of
Science. Searches were conducted using TSC search term
variations and keywords encompassing each of the six
levels of TAND. TSC and TAND level search terms were
combined with the Boolean operator ‘AND’, as outlined
in Additional file1.
Study selection
e titles and abstracts of the returned searches were
screened for relevance according to the following inclu-
sion criteria: (1) scientific articles published in peer-
reviewed scientific journals (including case reports,
letters to editors, research letters and research com-
mentaries), (2) full-text access available, (3) TAND
level keywords included in the resource subject, (4) any
research methodology or study design containing pri-
mary TAND data (including theoretical and applied
basic research, descriptive studies, interventions, quali-
tative, quantitative and mixed method approaches) and
(5) relevant TSC study populations described (including
animal models, individuals with TSC, families/caregiv-
ers and healthcare providers). No language or date limi-
tations were imposed during initial screening or full-text
review. Exclusions were made if search returns were: (1)
related to non-TAND topics (e.g. genetic mechanisms of
TSC), (2) literature reviews, systematic reviews or meta-
analyses with no reference to primary TAND data, or (3)
obtained from grey literature resources with no reference
to primary TAND data (e.g. commentaries, reports, book
chapters or conference proceedings). Grey literature
is defined as work that is not formally published under
the control of commercial organisations (e.g. academic
journals [68]). Although there is increasing focus on the
value of including grey literature in systematic reviews
and meta-analyses to overcome publication bias [69],
there is less of an emphasis on its inclusion in scoping
reviews when synthesising what is broadly known about
a research topic. Only half of scoping reviews currently
include grey literature [70], with the allocation of time
and resources conserved for subsequent comprehensive
systematic reviews [71].
Based on this initial screening, 2245 search returns
were excluded, as titles did not reference TAND level
keywords. Following the removal of duplicates (n =
201) and search returns from reviews and grey literature
sources (n = 45), 350 records were considered for full-
text review. e inclusion and exclusion criteria outlined
above were also applied during the full-text review. e
two co-first authors (SV and SB) independently com-
pleted the full-text review process to verify the accuracy
of the screening procedure. Where eligibility of a study
was unclear, inclusion/exclusion criteria were discussed
between the main authors to reach consensus. When
consensus could not be reached (n = 9), inclusion or
exclusion was determined by the senior authors (AJ and
PdV). is resulted in the inclusion of 230 eligible stud-
ies in this scoping review (see Fig. 1). Full references of
all 230 included studies are provided in Additional file2.
Data charting
A table for data extraction was developed at the full-
text review stage, with study characteristics identi-
fied in accordance with the ten research questions
outlined. Given substantial differences in data that can be
extracted from animal studies, case studies (descriptive
non-statistical clinical observations) and cohort studies
(analytical observational or experimental designs with
single or multiple groups), three distinct data extraction
tables were utilised to allow for such differences in study
type. Studies were therefore distinguished according to
animal studies (30/230), case studies (47/230) and cohort
studies (153/230). Here, a distinction is made between
case and cohort studies, whereby case studies are in-
depth systematic evaluations of a single person or group
without the presentation of statistical data analyses, and
cohort studies involve groups of individuals with TSC
taking part in experimental, non-experimental, obser-
vational, follow-up and case review study designs where
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
group-level statistical data are presented. Data extraction
was performed by the co-first authors (50% SV and 50%
SB). It is important to note that studies could span mul-
tiple TAND levels and clusters (e.g. autism profile stud-
ies that also referenced behavioural dysregulation). For
this reason, results reported here can exceed the maxi-
mum number of studies per study type. For example,
there were 153 cohort studies in total and 93 reference
behavioural TAND level information and 71 reference
psychiatric TAND level information. Some of these stud-
ies would have referenced both behavioural and psychi-
atric information. Results are therefore not summative
but reported as percentages of the total number of cohort
studies (93/153; 61% and 71/153; 46%), which can exceed
153 (100%). In relation to research question eight, behav-
iours reported as a consequence of an intervention (e.g.
fatigue and vomiting as adverse events of everolimus)
were not extracted as primary TAND data. However,
baseline pre-intervention behaviours (e.g. aggression,
self-injury) were extracted when reported.
Quality appraisal
To address research question four, the quality of all
230 included studies was evaluated. Animal studies
were appraised using the Animal Research: Reporting
of InVivo Experiments 2.0 guidelines (ARRIVE) [72],
and case studies and cohort studies were appraised
using the Mixed Methods Appraisal Tool (MMAT)
[73]. When utilising such tools, quantitatively rating
each criterion to establish an overall quality score is
discouraged. Instead, authors (SV, SB, NC, AVE) pro-
vided qualitative information for each criterion, and
studies were grouped according to quality based on
these descriptive summaries. For further information
regarding the grouping of studies according to quality,
please refer to Additional file3.
Inter‑rater reliability
Inter-rater reliability was established at study selec-
tion, data charting and quality appraisal stages accord-
ing to Cohen’s kappa coefficient (κ), where κ = (pope)
/ 1 – pe). Inter-rater reliability is considered good at
.61 and excellent at .81. Inter-rater reliability of
full-text screening between SV and SB was good (κ =
.709). Inter-rater reliability of data extraction content
for TAND levels and clusters was calculated for over
half of the included studies (128/230; 56%) to establish
whether the same information was reliably inferred.
Overall level of agreement between the co-first authors
Fig. 1 PRISMA flow diagram of study selection. Please note that articles are referred to as ‘records’ before full‑text screening and as ‘studies’ once
included in the review
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
(SV and SB) was excellent (animal studies: κ = 1.000,
case studies: κ = .827, cohort studies: κ = .839). Where
discrepancies in data extraction occurred, differences
were discussed and adjusted by consensus. Thirty
cohort studies, 10 case studies and 6 animal studies
(46/230; 20% of all included studies) were assessed for
quality by the co-first author (SB) to establish quality
appraisal inter-rater reliability with the primary raters
(SV, NC, AVE). Inter-rater reliability was excellent for
case studies (κ = .857), fair for cohort studies (κ =
.277) and moderate for animal studies (κ = .423).
Results
Research question 1: howmuch TAND research hasbeen
done overtheyears?
A total of 230 articles were identified that met the inclu-
sion criteria for the review. As shown in Fig. 2, three
case reports were published in 1987 describing intellec-
tual ability and autism profiles [7476]. In 1991, two UK
cohort studies describing the behavioural, intellectual
and academic levels of TAND were published by Webb;
the first paper profiling intellectual ability and autism
in TSC [77] and the second utilising magnetic reso-
nance imaging (MRI) to explore the neuroimaging pro-
file of children and adults of ‘normal intellect’ [78]. It is
important to note, several earlier TAND papers outlined
in Table1 (e.g. [25, 29]) were not identified during the
search. e first animal studies of TAND were published
in 2006 [79, 80]; both explored memory processing in the
Eker rat, a naturally occurring Tsc2+/- rat model. Taking
together animal, case and cohort studies, Fig.2 shows a
clear increase in TAND research, which is particularly
pronounced from 2013 onwards (118/230; 51%) after the
term TAND was coined in 2012.
Research question 2: wherehasTAND research been done
intheworld?
Countries were categorised as either a high-income country
(HIC) or low–middle-income country (LMIC) according to
the World Bank List of Economies [81]. Here, geographi-
cal location refers to the countries where participants were
recruited from, as opposed to the nationality or academic
institution of listed authors. Geographical information was
derived from the methods section of each study, as opposed
to listed author information that may have included inter-
national co-author collaboration. International multi-
site studies include multiple research sites as participants
were actively recruited from several countries; therefore,
the number of research sites exceeds the total number
of included studies. e majority of research, regardless
of study type, came from HIC research sites (see Table5).
Efforts to include LMICs in TAND research has mainly
Fig. 2 Number of TAND studies across years based on study type. *The search was completed in March 2020. As a result, the column does not
represent all TAND studies published in 2020
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
been led by five international multisite studies in recent
years [11, 19, 57, 61, 82]. Samples derived from community-
based approaches largely involved European and American
cohorts (e.g. Stichting Tubereuse Sclerosis Nederland, TSA
UK, TSC Alliance USA). Only nine studies used a general
population sample [34, 37, 8389]. Of these, all were popula-
tion-based studies from HICs (Italy, Sweden, UK, and USA).
e geographical locations of all 230 studies included in the
scoping review (represented as 341 individual research sites)
are presented in Fig.3 and Table6.
Overall, 341 individual research sites across 45 coun-
tries conducted TAND research. However, 41% of all
TAND research was derived from just two countries: the
USA (89/341; 26%) and the UK (50/341; 15%). Of note,
no TSC animal studies came from the UK. A significant
proportion of cohort participant research sites were
located in Germany, Italy and the Netherlands. Countries
defined as LMICs (Argentina, China, Colombia, Croatia,
Egypt, India, Malaysia, Mexico, Pakistan, Romania, Rus-
sia, South Africa, Taiwan and Turkey) represented only a
small combined proportion of research site involvement
in published TAND research (48/341; 14%). Most LMICs
were represented predominantly by international mul-
tisite studies as previously mentioned, as well as single-
participant clinical case reports (e.g. [91]).
Research question 3: which TSC age groups have been
investigated?
As shown in Table 5, the majority of human TAND
research involved school-age children aged 4–10 years
and adolescent participant samples aged 11–19 years
Table 5 Study information of scoping review TAND s according to study type
a Studies could span multiple data extraction points (e.g. a study involving infants, children and adolescents); therefore, numbers and percentages reported within
each category can exceed the maximum number of studies per study type. Percentages reported as percentage of study type total (animal studies: n = 30, case
studies: n = 47, cohort studies: n = 153). N/A information not applicable to study type
Animal studies (n = 30) Case studies (n = 47) Cohort studies (n = 153)
Sample characteristics Species:
• Mice (n = 26; 87%)
• Rats (n = 4; 13%)
Sex:
• Male (n = 25; 53%)
• Female (n = 14; 30%)
• Multiple case series (n = 8; 17%)
Age distributiona:
• Infant 0–3 years (n = 9; 19%)
• Child 4–10 years (n = 18; 38%)
• Adolescent 11–19 years (n = 16; 34%)
• Adult 20–60 years (n = 17; 36%)
• Older adult 60+ years (n = 1; 2%)
Sex ratio reported:
• 130 (85%)
Age distributiona:
• Infant 0–3 years (n = 90; 59%)
• Child 4–10 years (n = 97; 63%)
• Adolescent 11–19 years (n = 96; 63%)
• Adult 20–60 years (n = 70; 46%)
• Older adult 60+ years (n = 24; 16%)
Sample size:
50 (n = 88; 58%)
• 51–100 (n = 28; 18%)
• 101–200 (n = 17; 11%)
• 201–500 (n = 13; 9%)
• 501–1000 (n = 4; 3%)
1001 (n = 3; 2%)
Mixed caregiver patient cohort:
• 7 (5%)
Clinical information Genetic information:
• TSC1 (n = 8; 27%)
• TSC2 (n = 22; 73%)
Epilepsy information provided:
• 39 (83%)
IQ information provided:
• 31 (66%)
Genetic confirmation provided:
• 11 (23%)
Epilepsy information provided:
• All (n = 110; 72%)
• Some (n = 14; 9%)
• None (n = 29; 19%)
IQ information provided:
• All (n = 93; 61%)
• Some (n = 21; 14%)
• None (n = 39; 26%)
Genetic confirmation provided:
• All (n = 26; 17%)
• Some (n = 34; 22%)
• None (n = 93; 61%)
World Bank Classification HIC (n = 30; 100%)
LMIC (n = 0; 0%)
Multisite HIC and LMIC N/A
HIC (n = 33; 70%)
LMIC (n = 14; 30%)
Multisite HIC and LMIC N/A
HIC (n = 138; 90%)
LMIC (n = 10; 7%)
Multisite HIC and LMIC (n = 5; 3%)
Sample identificationaN/A N/A Population (n = 9; 6%)
Clinical (n = 108; 71%)
Community (n = 47; 31%)
Quality rating Relatively high (n = 8; 27%)
High (n = 22; 73%) Relatively high (n = 16; 34%)
High (n = 31; 66%) Low (n = 4; 3%)
Adequate (n = 26; 17%)
Relatively high (n = 84; 55%)
High (n = 39; 25%)
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
across case studies (school-age children: 18/47; 38%,
adolescents: 16/47; 34%) and cohort studies (school-
age children: 97/153; 63%, adolescents: 96/153;
63%). In contrast, very few case studies described or
reported TAND manifestations in infants aged 0–3
years (9/47; 19%) and few case studies (1/47; 2%; [74])
or cohort studies (24/153; 16%) involving older adults
over the age of 60 years.
Research question 4: what istheoverall quality ofexisting
TAND research?
Based on the ARRIVE quality criteria, the majority of
animal studies were rated as relatively high (8/30; 27%)
or high quality (22/30; 73%). As outlined in Table 5,
most case studies and cohort studies provided epilepsy
and intellectual ability information of their participants;
however, the number of individuals who received genetic
Fig. 3 World map depicting the geographical location of the 341 research sites identified across the 230 studies. Darker colours depict a greater
number of research sites per country
Table 6 Number of TAND studies according to country (and study type)
Countries listed in alphabetical order. A animal studies, CS case studies, CO cohort studies. Three hundred forty-one individual research sites across 230 studies
depicted according to country, as multisite large-scale registry studies are also represented (e.g. Long-term, Prospective Study Evaluating Clinical and Molecular
Biomarkers of Epileptogenesis in a Genetic Model of Epilepsy—Tuberous Sclerosis Complex (EPISTOP) and TuberOus SClerosis registry to increase disease Awareness
(TOSCA)). Please note that specic European countries described in one study as ‘other European countries’ are not represented [90]
Countries Total (A, CS,
CO)Countries Total (A, CS,
CO)Countries Total (A, CS,
CO)Countries Total (A, CS,
CO)Countries
(S‑U) Total (A, CS,
CO)
Argentina 1 (0, 0, 1) Denmark 4 (0, 0, 4) Israel 3 (0, 0, 3) Norway 4 (0, 0, 4) South Africa 5 (0, 0, 5)
Australia 9 (2, 0, 7) Egypt 1 (0, 0, 1) Italy 18 (1, 1, 16) Oman 2 (0, 2, 0) South Korea 8 (0, 2, 6)
Austria 4 (0, 0, 4) Estonia 3 (0, 0, 3) Japan 10 (1, 3, 6) Pakistan 1 (0, 1, 0) Spain 6 (0, 0, 6)
Belgium 6 (0, 0, 6) France 9 (0, 2, 7) Latvia 3 (0, 0, 3) Poland 10 (0, 1, 9) Sweden 5 (0, 0, 5)
Canada 7 (2, 0, 5) Germany 14 (6, 0, 8) Lithuania 3 (0, 0, 3) Portugal 4 (0, 0, 4) Taiwan 6 (0, 0, 6)
China 10 (0, 1, 9) Greece 4 (0, 0, 4) Malaysia 1 (0, 0, 1) Romania 3 (0, 0, 3) Thailand 4 (0, 0, 4)
Colombia 1 (0, 0, 1) Hungary 1 (0, 0, 1) Mexico 1 (0, 0, 1) Russia 4 (0, 0, 4) Turkey 4 (0, 0, 4)
Croatia 1 (0, 1, 0) India 9 (0, 9, 0) Netherlands 14 (0, 1, 13) Slovakia 3 (0, 0, 3) UK 50 (0, 5, 45)
Czech
Republic
5 (0, 0, 5) Ireland 1 (0, 0, 1) New Zealand 1 (0, 1, 0) Slovenia 3 (0, 0, 3) USA 89 (21, 12, 56)
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
confirmation of their diagnosis in case studies and cohort
studies within this scoping review was relatively low. e
majority of cohort studies (88/153; 58%) involved fewer
than 50 participants. Based on the MMAT quality crite-
ria for human studies, the majority of case studies (31/47;
66%) were of high quality, although most case studies did
not meet criteria for inclusion of a representative sample.
Cohort studies showed more variation in study quality
(see Table5 and further comments in the Discussion).
Research question 5: which TAND levels have been
investigated?
TAND level focus was analysed according to study type
(see Fig. 4). e psychiatric, intellectual, academic and
psychosocial levels of TAND were not relevant to ani-
mal studies. e majority of animal research focused
on behavioural manifestations in mice and rats (28/30;
93%), such as social approach behaviours (e.g. [92]), anxi-
ety (e.g. [93]), and social–communication behaviours
associated with autism (e.g. [49]). Several animal stud-
ies focused on the neuropsychological level (16/30; 53%),
as previously mentioned, particularly aspects relating
to spatial processing, motor learning and memory (e.g.
[94]). In human studies, both case and cohort studies
predominantly reported on the behavioural (case studies:
40/47; 85%, cohort studies: 93/153; 61%) and intellectual
levels (case studies: 42/47; 89%, cohort studies: 124/153;
81%).
Relatively few case or cohort studies reported aca-
demic (case studies: 19/47; 40%, cohort studies: 38/153;
25%), neuropsychological (case studies: 20/47; 43%,
cohort studies: 60/153; 39%), or psychosocial informa-
tion (case studies: 11/47; 23%, cohort studies: 35/153;
23%). It is important to note that although there were few
psychosocial level studies overall, those that existed did
specifically outline quality of life (e.g. [95]) or caregiver
experiences (e.g. [96]) as a primary focus of the research,
as evidenced by the study titles. By contrast, studies
reporting academic information did not primarily focus
on schooling or learning experiences of individuals with
TSC. Academic information was briefly addressed as
part of the larger participant or demographic informa-
tion reporting, rather than as a primary research aim (e.g.
[97]).
Research question 6: which research methods andresearch
measures have been used toinvestigate TAND?
A range of research methodologies have been used in
TAND research to date (see Table 7). Animal studies
exploring the behavioural and neuropsychological levels
of TAND utilised a number of direct behavioural assess-
ments (28/30; 93%) and neurobiological techniques in
Fig. 4 Research of different TAND levels based on study type (animal, case studies, cohort studies). The psychiatric, intellectual, academic and
psychosocial levels were not applicable to animal studies and were therefore not shown
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
conjunction with behavioural assessments (23/30; 77%),
such as immunohistochemistry and electroencephalog-
raphy (EEG), to explore aspects relating to behaviour,
learning and memory. Animal studies utilised standard-
ised behavioural assessment protocols to explore aspects
relating to behaviour and neuropsychological function-
ing. Such protocols included social versus inanimate
object preference tests of social approach behaviours,
marble burying to explore repetitive behaviour profiles,
open-field tests of anxiety-related behaviours and ‘Mor-
ris water maze’ tasks to test spatial learning and memory
processes.
In human studies, case studies largely focused on medi-
cal record reviews of behaviour and psychiatric diagnoses
(41/47; 87%), neuroimaging techniques such as EEG
and MRI (42/47; 89%), and physiological examinations
of tumour growth, seizures and physical health condi-
tions in accordance with psychosocial manifestations
(39/47; 83%). When exploring behavioural and intellec-
tual aspects of TAND, case studies largely used retro-
spective or informant-report methodologies (e.g. case
notes or caregiver report), as opposed to direct in-person
methods of assessment (e.g. the Wechsler Adult Intelli-
gence Scale, fourth edition [98]). It is important to note
that few case studies provided specific details regarding
the exact measures used, either from retrospective medi-
cal reviews, or when reporting on direct assessments
(e.g. stating only ‘a comprehensive neuropsychology
Table 7 Research design and methodology of scoping review TAND studies
a Studies could span multiple data extraction points (e.g. a study that included an IQ assessment, direct behavioural assessment and neuroimaging); therefore,
numbers and percentages reported within each category can exceed the maximum number of studies per study type. Percentages reported as percentage of total
study type total (animal studies: n = 30, case studies: n = 47, cohort studies: n = 153). N/A information not applicable to study type
Animal studies (n = 30) Case studies (n = 47) Cohort
studies (n =
153)
Study designa
Quantitative 30 (100%) 12 (26%) 147 (96%)
Qualitative N/A 45 (96%) 13 (9%)
Descriptive 42 (89%)
‘Typically qualitative’ 3 (6%)
Control group (e.g. typically developing) N/A N/A 23 (15%)
Contrast group (e.g. genetic syndrome) N/A N/A 15 (10%)
Multiple control and contrast groups N/A N/A 5 (3%)
Methodologya
Medical record review N/A 41 (87%) 67 (44%)
Standardised questionnaires N/A 3 (6%) 52 (34%)
Interviews (standardised/clinical/research) N/A 0 (0%) 38 (25%)
Clinical report N/A 1 (2%) 0 (0%)
Neuroimaging 23 (77%) 42 (89%) 74 (48%)
Direct neuropsychological assessment N/A 12 (26%) 33 (22%)
IQ assessment N/A 17 (36%) 80 (52%)
Direct behavioural assessment 28 (93%) 27 (57%) 9 (6%)
Physiological examination 14 (47%) 39 (83%) 35 (23%)
Diagnostic assessment N/A 15 (32%) 51 (33%)
TAND Checklist N/A 1 (2%) 6 (4%)
Remote methodologya
Online survey N/A 0 (0%) 9 (6%)
Telephone interview measures N/A 0 (0%) 4 (3%)
Mobile application N/A 0 (0%) 0 (0%)
Interventiona
Non‑pharmacological 15 (50%) 8 (17%) 0 (0%)
Pharmacological 24 (80%) 15 (32%) 8 (5%)
mTORi 14 (47%) 7 (15%) 5 (3%)
Other 4 (13%) 0 (0%) 4 (3%)
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
assessment’). Case studies also rarely utilised robust
research tools, such as standardised questionnaires (3/47;
6%; [99101]) or standardised interviews (0/47; 0%). e
three case studies that utilised standardised question-
naires used measures such as the Aberrant Behaviour
Checklist [102], the Social Responsiveness Scale, sec-
ond edition [103] and the Behaviour Rating Inventory of
Executive Function [104]. Only one case study included
the TAND Checklist as an assessment measure [105].
Compared with case studies, cohort studies utilised
more direct in-person methods of assessment, includ-
ing direct IQ assessments (80/153; 52%), and diagnostic
assessment tools (51/153; 33%). However, few cohort
studies conducted any specific behavioural assessments
(9/47; 6%). Of the nine studies identified [106114],
seven utilised screening measures for autism, such as the
Autism Observation Scale for Infants (AOSI; [115]) and
the Childhood Autism Rating Scale [116], two reported
on specific behavioural items from the Autism Diag-
nostic Observation Schedule, second edition (ADOS-2;
[117]), one involved a semantic decision task [96], and
one explored musicality using a behavioural test battery
[118]. Here, the ADOS-2 was considered a behavioural
assessment as well as a diagnostic assessment when item-
level analysis of the ADOS-2 was also conducted. e
AOSI was considered a screening measure for ‘risk mark-
ers’ of autism in toddlers under the age of 18 months,
before the age of typical autism diagnosis, and is there-
fore not considered a diagnostic instrument. Cohort
studies largely utilised standardised questionnaires
(52/153; 34%) and interviews (38/153; 25%), including
standardised interviews such as the Vineland Adaptive
Behaviour Scales, second edition [119], as well as clinical
interviews and semi-structured research interviews (e.g.
[120]). Cohort study diagnostic tools largely explored the
profile of autism and psychiatric conditions. It is impor-
tant to note that studies reporting on psychiatric comor-
bidities (e.g. [121, 122]) were largely based on psychiatric
or clinical evaluation, and the specific details of diag-
nostic measures used were not provided. IQ measures
included assessments such as the Bayley Scales of Infant
Development, second edition [123] and the Wechsler
Intelligence Scale for Children, third edition [124]. Since
its publication in 2015, six cohort studies have utilised
the TAND Checklist as an assessment measure [11, 19,
57, 61, 125, 126]. ree of these six studies reported data
from the TOSCA registry [11, 19, 57].
Research question 7: howmuch quantitative
andqualitative TAND research hasbeen conducted?
When referring to case studies, research was considered
quantitative when within-group or follow-up descriptive
statistics were reported. A distinction was made between
case studies that were ‘typically qualitative’ (e.g. thematic
analysis, focus groups) and case studies that were more
‘descriptive’ in nature (e.g. detailed family history, clini-
cal opinion), as summarised in Table7. e majority of
case studies were ‘descriptive’ (42/47; 89%) as opposed to
‘typically qualitative’ (3/47; 6%). Of these, two included
direct quotes from participants [127, 128], and one out-
lined qualitative themes based on a caregivers viewpoint
[129]. Cohort studies were predominantly quantitative
(147/153; 96%). Quantitative cohort studies were more
likely to be descriptive single TSC cohort designs as
opposed to experimental randomised control trials or
between-group designs, as the majority of TAND cohort
studies in this scoping review did not utilise contrast or
control groups (110/153; 72%). irteen of the 153 cohort
studies (9%) were qualitative [37, 54, 84, 120, 130138].
Of these, only two included self-report interviews with
individuals themselves with TSC, the others were quali-
tative perspectives of parents/caregivers [54, 134].
Research question 8: howmany intervention studies have
been conducted?
A relatively high number of animal studies (26/30; 87%)
and case studies (25/47; 53%) utilised interventions
(see Table 7). Please note, data extraction only consid-
ered baseline reporting of TAND level information, not
adverse effects or changes in TAND as a consequence
of medication or treatment. Few cohort studies involved
interventions (16/153; 11%). Of these 16 cohort inter-
vention studies, five studies were everolimus clinical tri-
als that explicitly considered TAND outcomes [50, 51,
82, 135, 139], five studies explored effects of antiepilep-
tic medications [83, 140143], two studies explored the
effects of melatonin on sleep [144, 145], and four studies
encompassed ‘other’ forms of intervention; the ketogenic
diet [146], epilepsy surgery [147], ablation of tumours
[148] and provision of information resources to aid
parental understanding of TSC [138]. To date, no cohort
studies have utilised non-pharmacological interventions
in TSC.
Research question 9: have remote technologies been
utilised tostudy TAND?
Within human studies, the use of remote methodologies
was low (see Table7). No case studies utilised remote
methods of data collection, compared with very few
cohort studies (13/153; 8%). Of these 13 cohort studies,
11 studies specifically explored the psychosocial level of
TAND in relation to caregiver experiences and quality of
life variables, seven using online surveys [52, 90, 96, 131,
149151] and four using telephone interviews [120, 134,
137, 147]. Two studies utilised online surveys to explore
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
the behavioural and psychiatric levels of TAND, includ-
ing sleep and behaviour in children [152] and mental
health presentation and service provision in adults [153].
To date, no studies have utilised other technologies such
as mobile applications, video conferencing, sensing tech-
nologies or robotics in TAND research.
Research question 10: which TAND clusters have been
studied?
Given the recent identification of natural TAND clus-
ters, we were keen to determine the proportion of TAND
research to date that has been performed in relation to
these clusters. e TAND Checklist was only published
in 2015 [13], and natural TAND clusters were only
described in 2018 [61]. erefore, it is important to note
many publications in this scoping review may have used
other terminologies that do not easily group into each of
the seven natural TAND clusters. Evidently, there were
relatively few publications that did not specifically fall
into cluster groups across animal studies (0/30; 0%), case
studies (2/47; 4%) or cohort studies (13/153; 8%). Across
all study types, the majority of studies referenced multi-
ple clusters per paper (animal studies = 20/30; 67%, case
studies = 39/45; 87%, cohort studies = 95/140; 68%). e
45 cohort studies that explored only single clusters within
each paper largely focused on the neuropsychological
cluster (14/45; 31%) or the autism spectrum disorder–
like cluster (19/45; 42%).
As shown in Fig.5, the majority of animal studies refer-
enced the autism spectrum disorder–like cluster (20/30;
67%), the neuropsychological cluster (16/30; 53%) and
the mood/anxiety cluster (16/30; 53%). Very few animal
studies explored dysregulated behaviour (3/30; 10%; [48,
94, 154]), eat/sleep (3/30; 10%; [48, 154, 155]) or the over-
active/impulsive clusters (2/30; 7%; [154, 156]). In human
studies, both case studies (30/47; 64%) and cohort stud-
ies (88/153; 58%) largely focused on the autism spectrum
disorder–like cluster, but infrequently referenced scho-
lastic information (case studies: 16/47; 34%, cohort stud-
ies: 37/153; 24%). Across all TAND clusters, the eat/sleep
cluster was the most under-researched in cohort studies
(35/153; 23%).
Discussion
e term ‘TAND’ was first coined in 2012 and published
in 2013 [8] in an effort to reduce the clinical identifica-
tion and treatment gap for the behavioural, psychiatric,
intellectual, academic, neuropsychological and psycho-
social manifestations associated with TSC, and to gen-
erate a ‘shared language’ that could aid global research
efforts. is comprehensive scoping review was the first
to synthesise the TAND research landscape using ten
Fig. 5 Research on different TAND clusters based on study type (animal, case studies, cohort studies). The scholastic cluster was not applicable to
animal studies and was therefore not shown
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Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
Table 8 Main findings and directions for future TAND research
Research question Main ndings Directions for future research
1. TAND research
across years The number of TAND studies has increased over time,
particularly since the term TAND was coined Systematic reviews of each cluster should be conducted to capture
TAND research that may have been missed
2. TAND research
location TAND research is predominantly conducted in HICs, the
majority of HIC‑led TAND research occurs in the USA and
the UK
More research is needed particularly in South American, Middle
Eastern, African, South‑East Asia and Western Pacific countries
TAND research is only evident in some LMICs due to
representation from larger HIC‑led multisite studies (e.g.
Argentina, Mexico, Romania)
More TAND‑focused research is needed that originates from LMICs
reflecting specific cultural contexts, as opposed to research that
only includes LMICs as part of larger multisite studies
3. Age distribution The majority of human TAND research involves school‑
age and adolescent samples, with fewer studies includ‑
ing infant (0–3 years) or older adult samples (60 years
and over)
Research that specifically focuses on the presentation of TAND
across the lifespan and longitudinal research that investigates
changes in TAND across developmental stages are needed
4. Study quality Most case and cohort studies provide epilepsy and intel‑
lectual ability information but TSC genetic confirmation
in studies is relatively low
TAND researchers should be encouraged to include data on sei‑
zures, intellectual ability and TSC genotype where possible
The majority of TAND cohort studies involve fewer than
50 participants Large‑scale, coordinated cohort studies involving multisite interna‑
tional collaboration should be considered, except where specific
research questions warrant small samples
Animal studies and case studies are rated as high or
relatively high quality; however, there is considerable
variability in the quality of cohort studies, perhaps as a
consequence of the quality appraisal tool used
Development of a scoping review quality appraisal tool will be
beneficial to aid in the interpretation of study quality that allows for
cross‑comparison between different study designs
5. TAND levels Animal studies largely report on the behavioural level of
TAND More contemporary animal research is needed that explores the
neuropsychological level of TAND
Case studies and cohort studies largely report on behav‑
ioural and intellectual TAND levels In human studies, research is needed that focuses on the academic,
neuropsychological and psychosocial levels of TAND
6. Research methods
and measures Animal studies utilise behavioural protocols and neuro‑
imaging techniques More TSC animal model research is needed that specifically utilises
behavioural protocols that are relevant to TAND
Case studies largely employ medical record reviews
neuroimaging and physiological examinations, but rarely
utilise standardised research assessments
TAND case studies would benefit from the inclusion of standard‑
ised assessments where possible and description of assessments
completed as part of a clinical evaluation
Cohort studies utilise IQ assessments and diagnostic
research measures of autism More direct behavioural assessments and behavioural observations
in TAND research is needed, as well as a need to outline which
specific diagnostic measures have been utilised when reporting
TAND information based on psychological evaluation
As a recently published measure, the TAND Checklist is
rarely used as an assessment tool in human research Human studies would benefit from the inclusion of TAND Checklist
reporting where applicable
7. Quantitative and
qualitative research There are relatively few qualitative cohort studies Qualitative research will be useful to refine the phenomenology of TAND
behaviours that are not well‑characterised in the existing literature
The few qualitative studies that exist largely explore the
psychosocial level More qualititative research is needed that explores the under‑
researched areas of TAND
The majority of quantitative cohort studies are descrip‑
tive as they do not utilise contrast or control groups TAND cohort studies would benefit from the utilisation of appropri‑
ate control and contrast groups to determine TSC‑specific manifes‑
tations of behaviours
8. Interventions There are very few published intervention cohort stud‑
ies, with a notable absence of any non‑pharmacological
intervention studies
Intervention studies are needed that take into account TAND
outcomes, particularly exploring the effectiveness of non‑pharama‑
cological interventions in relation to TAND
9. Remote technologies Only a small minority of cohort studies have employed
remote methods of data collection, those that do largely
explore the psychosocial level
Studies utilising remote technologies (e.g. mobile applications,
video conferencing, online surveys) may help address TAND knowl‑
edge gaps and increase LMIC and population‑based research
10. TAND clusters A number of TAND clusters are under‑researched in
animal studies More TSC animal models are needed that explore the dysregulated
behaviour, overactive/impulsive and eat/sleep clusters
Across human studies, the scholastic cluster is relatively
under‑researched TAND clusters that are under‑researched may be difficult to assess
or quantify, and efforts should be made to evaluate existing assess‑
ments and tools to determine their utility in TSC cohorts
The autism spectrum disorder–like cluster is the most
widely researched across all three study types Human studies would benefit from TAND‑specific research that
explores under‑researched clusters, specifically the scholastic and
eat/sleep clusters in TSC cohorts
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Page 16 of 23
Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
broad research questions. A summary of the findings and
proposed directions for future research are outlined in
Table8. It was encouraging to see that there has been a
clear increase in TAND research outputs in recent years,
which may correspond with the adoption of ‘TAND’ ter-
minology, and increased awareness of the TAND identi-
fication gap [8, 13, 14]. Despite the increase, a number of
particular areas of TAND research warrant further inves-
tigation. In addition, the nature of a scoping review is to
focus on ‘topline’ questions. To complement this review,
in-depth content reviews within individual TAND clus-
ters are warranted.
Regarding the location of research, current TAND
studies seems to over-represent TSC populations in HICs
and may therefore not be generalisable or applicable to
all global communities, such as in South America, the
Middle East, Africa, and the Asia-Pacific region. In par-
ticular, very little research has been performed in LMICs.
e socioeconomic, cultural and contextual factors that
influence TAND identification and treatment in LMICs
are therefore largely under-represented in the current
TAND literature. Under-represented factors include but
are not limited to: mental health service provision [157],
access to autism diagnosis and screening assessments
[158], disparities in the educational attainment of dis-
ability populations [159], and sociocultural differences in
the epidemiology of eating disorders [160]. Where cohort
studies included LMICs as part of international patient
registries, it was unclear how much contribution LMICs
had to study design or cultural translation, or the extent
to which selection bias towards more severe/rare presen-
tations of the disorder was evident [11]. Given that the
majority of the world’s population live in LMICs, future
research should place a particular emphasis on fostering
LMIC-led TAND studies representative of the research
needs and cultural context of individual countries.
In relation to the age distribution of TAND research
participants, not many case studies described TAND
level behaviours in infants, while cohort studies of infants
mainly focused on autism presentation and related neu-
rodevelopmental disability in relation to seizures. A
broadening of infant research across TAND levels and
clusters may therefore be a helpful next step. e number
of case studies and cohort studies involving older adults
was also low. From baseline data in the TOSCA regis-
try, the oldest participant was 71 years old. However, it
appears that most older adults living now with TSC may
not have a confirmed genetic diagnosis [57] and there-
fore may not be represented within clinical population
samples, or be identified within TSC clinics. e limited
number of studies involving older adults may therefore
reflect a broader issue with under-diagnosis of older
individuals with rare genetic syndromes [161]. Given the
longitudinal research indicating persistent TAND mani-
festations over time (e.g. [162, 163]), more research on
TAND in older adults and across the developmental lifes-
pan in general would be important. is includes exami-
nation of TAND associated with neurodegenerative
processes, the relationship between changing seizure sta-
tus over time and neurocognitive outcomes and whether
an emergence or change in TSC physical characteristics
(e.g. renal angiomyolipomas) is associated with TAND
outcomes. is will be particularly important in relation
to aspects of TAND that are under-researched, including
the psychosocial level and eat/sleep cluster.
Study quality was difficult to establish, given the vari-
ability not only between study types (e.g. animal and
human studies), but also between study designs (e.g. ran-
domised controlled trials and quantitative descriptive
cohort studies). Consequently, inter-rater agreement was
low, particularly for cohort studies. It was also not pos-
sible to compare quality across cohort studies in a mean-
ingful way, given that methodological criteria differed
substantially according to study design (e.g. randomised
controlled trials were rated according to five criteria
that were non-comparable to the quantitative descrip-
tive criteria). e absence of a ‘one-size-fits-all’ quality
appraisal tool has long been recognised as a limitation in
the scoping review field [64]. As such, very few scoping
reviews endorse quality assessments [164], highlighting
the need for a simplified quality appraisal tool that tran-
scends multiple study designs and types. Small additions
in TAND research protocols such as inclusion of seizure,
IQ and genotype data, and generation of a core set of
sociodemographic data could be helpful to increase study
quality and determination thereof in future research.
Development of large-scale international TAND consor-
tia that uses high-quality, standardised measures have
the potential to transform TAND research in the coming
decades.
When examining research across TAND levels, it was
clear that academic, neuropsychological and psycho-
social aspects in individuals with TSC warrants further
investigation. Given the very limited use of standardised
assessment of specific learning skills (e.g. reading, writ-
ing, spelling, mathematics), an evaluation of suitable
measures of scholastic ability (e.g. picture-based seman-
tic association tests of vocabulary [165]) and reading and
spelling (e.g. the Wechsler Objective Reading Dimensions
test [166]) in diverse TSC populations, could be of signif-
icant value. Nevertheless, research on most TAND levels
could benefit from improvements in rigour, for example:
increased use of standardised behavioural ratings and
observations, use of standardised psychiatric diagnostic
schedules, IQ-based assessments in all individuals with
TSC, standardisation of neuropsychological evaluations
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Page 17 of 23
Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
including ‘bedside’ neuropsychological assessments,
and expansion of psychosocial research to differentiate
between the impact of TSC and TAND on individuals
and their caregivers.
Comparison of qualitative versus quantitative research
in TAND exposed a disproportionately high representa-
tion of quantitative studies compared with qualitative
studies across all TAND levels. Of the 13 qualitative stud-
ies included in this scoping review, eight considered the
psychosocial level [54, 120, 131134, 137, 138]. Of those,
only one was derived from a LMIC (South Africa; [138]).
Herein lies two directions for future research. First, more
qualitative research overall is needed that explores qual-
ity of life variables, health-related burden and caregiver/
sibling impact. Qualitative research that specifically aims
to include the voices of individuals living themselves
with TSC would be particularly valuable. Second, the
psychosocial impact of a neurodevelopmental disorder
is strongly influenced by contextual factors, which may
include sociopolitical, cultural and economic contribu-
tors, amongst others. In order to ensure that we develop
a global understanding of TAND, further qualitative
research is required across HICs and LMICs [167].
Interventional research was very limited across case
studies and cohort studies. Case studies mostly refer-
enced the prescription of medications, most notably the
mTORi everolimus. Examples of non-pharmacological
interventions in case studies included cognitive behav-
ioural therapy for obsessive compulsive disorder [127],
‘behavioural extinction’ for aggression [168] and ‘cog-
nitive retraining’ techniques for mood, attention and
behaviour [128]. In contrast, no cohort study in the
review described non-pharmacological interventions.
Following the completion of searches for this scoping
review in March 2020, a protocol has since been pub-
lished for a naturalistic developmental behavioural inter-
vention (NDBI) for social communication in infants with
TSC based on JASPER (Joint Attention, Symbolic Play,
Engagement and Regulation [169, 170]), the results of
which will significantly contribute to our understand-
ing of intervention-based research for TAND. Future
research should prioritise exploring the effectiveness of
existing non-pharmacological interventions in TSC. is
may be of particular value in the autism spectrum dis-
order–like cluster, where there is a strong evidence base
for NDBIs, and within the dysregulated behaviour and
mood/anxiety clusters, where existing cognitive/behav-
ioural interventions have demonstrated marked success
in individuals with autism [171, 172]. It should be noted
that time and distance are significant barriers to enrol-
ment in non-pharmacological intervention studies, as
evident upon reflection of the JASPER TSC intervention
[173].
In light of the COVID-19 pandemic, a move towards
remote methods of assessment and intervention, as well
as mobile health (mHealth) applications, demonstrates
both practical and methodological sense. For this reason,
we included a specific research question about the use
of remote modalities. Our results showed a very limited
number of studies that had used telephone interviews
(e.g. [147]) and online surveys (e.g. [150]) for data collec-
tion. It was therefore very encouraging to see the innova-
tive approach of the JASPER study outlined above using
remote technologies for intervention delivery.
In an ongoing project (‘Empowering families through
technology: a mobile-health project to reduce the TAND
identification and treatment gap’) referred to as the TAN-
Dem project, the TAND consortium is aiming to address
a number of TAND research gaps by using digital tech-
nologies. One of the key aims of the project is to develop
a self-report quantified version of the TAND Checklist,
the TAND-SQ, built into a ‘TAND toolkit’ mobile appli-
cation (http:// www. tandc onsor tium. org). We propose
that significant resources should be allocated to the
development of digital/mHealth applications that could
facilitate TAND research (e.g. through remote data col-
lection), research capacity-building (e.g. through build-
ing of a global network of TAND researchers), as well
as leading to direct clinical impact through provision of
training and fostering a shared language and understand-
ing of TAND within clinician–patient relationships. Use
of remote technologies could address many of the TAND
research gaps identified in this scoping review, includ-
ing low representation from LMICs, limited publication
of qualitative TAND research and a need for non-phar-
macological interventions involving TSC community
populations.
e review gives weight to the complex and multifac-
eted nature of TSC, given that the majority of TAND
studies were multi-cluster focused. Research therefore
reflects the natural grouping of co-occurring TAND
manifestations, and very few studies did not adhere to
this seven-factor structure [63]. ose that did not cor-
respond to an individual cluster (e.g. [174]) were studies
that largely explored the intellectual level of TSC without
reference to co-occurring behaviours or clinical condi-
tions. Few studies focused on an individual cluster in spe-
cific detail, without reference to other clusters. As many
TAND clusters are comparatively under-researched (e.g.
scholastic, overactive/impulsive, eat/sleep), future TAND
research may aim to specifically target these individual
clusters for focused analysis. In animal research, inves-
tigation of dysregulated behaviours, eat/sleep, mood/
anxiety and other neuropsychological skills (e.g. atten-
tion, dual tasking, planning) could provide valuable
fundamental insights into the biological underpinnings
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Page 18 of 23
Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
and potential treatments within these TAND clusters.
In human studies, highly under-explored clusters could
employ qualitative designs as a first step towards refining
phenomenology of behaviours that remain poorly under-
stood in TSC, such as temper tantrums [175] or eating
behaviours. Ensuring that the obvious research gaps in
TAND clusters are filled with high-quality research in
the coming decades will lead to significant improvements
in clinical care for families and individuals who live with
TSC and TAND.
Limitations
We acknowledge a number of limitations in the cur-
rent study. First, the inclusion or exclusion of studies
at full-text level did not depend on any quality assess-
ment. This step, which is in line with the scoping
review methodology, might lead to a distorted view
of the quality of evidence discussed here. Similarly,
although we did not impose a language restriction on
our searches, most of the resources found were writ-
ten in English. These observations should primarily
be understood as important findings of this scoping
review and a key indication of the geographical distri-
bution in relation to existing TAND research. We also
did not determine whether the included manuscripts
had a primary focus on TAND or whether TAND was
a secondary or coincidental component of the work.
Second, iterative search actions conducted after mul-
tiple consultations with other researchers or experts
could have yielded other results than the consecu-
tive search approach we utilised in the present study.
Nevertheless, we are convinced that we have obtained
the most comprehensive search results in the field to
date to synthesise existing TAND research. Third, we
are aware that our broad description and evaluation of
the TAND research field lacks an in-depth discussion
of the results. A more profound exploration of specific
findings (e.g. an in-depth evaluation of animal study
research in relation to TAND, a detailed analysis of
standardised assessments employed by cohort studies,
further consideration of specific TAND cluster items)
may reveal other points for discussion or directions for
future research. In this regard, this exploratory scop-
ing review should be considered a roadmap for future
TAND studies, including future reviews of the litera-
ture. Finally, as outlined in the Results section, there
are several high profile or historical papers referenced
in Table1 that have not been captured by this scoping
review. There are several reasons why their absence
from the database searches may have occurred. Histor-
ical papers on online databases are primarily scanned
hard copies from original journals, and therefore, elec-
tronic searches sometimes do not capture abstract
content. Alternatively, it may be possible that search
terms utilised here may not have reflected the his-
torical language used by older studies (e.g. epiloia or
Bourneville’s disease as synonyms for TSC), or that
our current search terms were too stringent to capture
more general descriptions of TSC neuropsychiatric
conditions. We therefore recommend detailed cluster-
based systematic reviews as a useful next step, with a
particular emphasis and consideration on the inclusion
of grey literature where appropriate.
Conclusion
Although TAND research output has increased in recent
years, significant gaps in knowledge remain. Overall, we
observed an imbalance in TAND research across TAND
levels and TAND clusters, with some levels (e.g. intel-
lectual) and clusters (e.g. autism spectrum disorder–like
cluster) much more widely researched than other aspects
of TAND (e.g. scholastic skills and dysregulated behav-
iour). ere is a clear need for future cohort studies that
consider the presentation of TAND in older adult popu-
lations and qualitative methods to explore the phenom-
enology of behaviours that are poorly defined in TSC.
Future research also needs to address the geographical
disparities in TAND research that currently over-rep-
resents HIC involvement and under-represents LMICs.
A move towards intervention is warranted, particularly
non-pharmacological interventions that address TAND
manifestations. e utilisation of specific remote meth-
odologies, such as mobile applications and video confer-
encing technology will go some way to addressing several
of the TAND research gaps identified here. International
collaboration involving LMICs and utilisation of remote
technologies are key aspects of the TANDem project,
which aims to address the TAND identification and treat-
ment gap in LMICs and alter the current TAND research
landscape.
Abbreviations
ADHD: Attention deficit hyperactivity disorder; ADOS‑2: Autism Diagnostic
Observation Schedule, Second Edition; AOSI: Autism Observation Scale for
Infants; ARRIVE: Animal Research Reporting of In Vivo Experiments; DSM‑5:
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; EEG:
Electroencephalography; EPISTOP: Long‑term, Prospective Study Evaluating
Clinical and Molecular Biomarkers of Epileptogenesis in a Genetic Model of
Epilepsy—Tuberous Sclerosis Complex; GRIPP: Global regulator and integrator
of a range of physiological processes; HIC: High‑income country; ICD‑11:
International Classification of Diseases and Related Health Problems, Eleventh
Edition; JASPER: Joint Attention Symbolic Play Engagement and Regula‑
tion; LMIC: Low–middle income country; mHealth: Mobile health; MMAT:
Mixed Methods Appraisal Tool; MRI: Magnetic resonance imaging; mTOR:
Mammalian/mechanistic target of rapamycin; mTORi: mTOR inhibitor; NDBI:
Naturalistic developmental behavioural intervention; TAND: TSC‑associated
neuropsychiatric disorders; TANDem: Empowering families through technol‑
ogy: a mobile‑health project to reduce the TAND identification and treatment
gap; TOSCA: TuberOus SClerosis registry to increase disease Awareness; TSA:
Tuberous Sclerosis Association; TSC: Tuberous sclerosis complex.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 19 of 23
Vancloosteretal. Journal of Neurodevelopmental Disorders (2022) 14:13
Supplementary Information
The online version contains supplementary material available at https:// doi.
org/ 10. 1186/ s11689‑ 022‑ 09423‑3.
Additional le1. TSC and TAND level search terms.
Additional le2. Two hundred thirty studies included in scoping review
according to study type.
Additional le3. Quality rating categorisation and grouping.
Acknowledgements
We acknowledge all people with TSC who have contributed to TAND research
over the years. We dedicate this review to Ann Hunt and Loren Leclezio who,
in their different ways, inspired the establishment of the TAND consortium
(http:// www. tandc onsor tium. org).
Authors’ contributions
SV, SB, AJ and PJdV conceptualised the study. SB and SV conducted the
literature searches, reviewed the extracted studies at title, abstract and full‑text
level and assessed study eligibility. SB, SV, AJ and PJdV reached consensus
on final included studies. SB, SV, AVE and NC assessed study quality. SB and
SV performed data charting and, with AJ and PJdV, performed analysis and
formatting of the manuscript. All authors contributed to interpretation of find‑
ings and to review and revision of the manuscript. All authors approved the
final manuscript prior to submission.
Funding
The work was funded by a grant from the King Baudouin Foundation Fund Dr
& Mrs Charles Tournay‑Dubisson to PJdV and AJ (2019‑J1120010‑213544) and
supplemental funding from the Tuberous Sclerosis Association (UK) (2019‑
P03) to PJdV.
Availability of data and materials
All data generated and analysed for the purpose of this review are included in
this publication and its supplementary information files.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
SB is funded by Cerebra to investigate sleep and behaviour in rare genetic syn‑
dromes, including TSC. PD receives partial salary support from the NIH for par‑
ticipation in studies related to TSC, as well as from Aucta Pharmaceuticals for
a study of topical sirolimus for facial angiofibromas in TSC and Marinus Phar‑
maceuticals for a study of ganaxolone for TSC‑related epilepsy. DAK reports
grants from National Institutes of Health (NINDS) during the conduct of the
study as well as the personal fees from Novartis Pharmaceuticals, personal fees
from Greenwich Bioscience, grants from Marinus Pharmaceuticals, personal
fees from Nobelpharma America, personal fees from REGENXBIO, and grants
and non‑financial support from TSC Alliance outside the submitted work. CS
receives salary support from the TSC Alliance, a non‑profit organisation which
reports revenue from individual donors and corporations including Greenwich
Biosciences, GW Pharma, Mallinckrodt, Nobelpharma, Novartis, Ovid, UCB and
Upsher‑Smith. PJdV was a study steering committee member of three phase
III trials sponsored by Novartis. He and AJ were also on the scientific advisory
group of the TOSCA international disease registry sponsored by Novartis.
MS reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio
and Aucta, and has served on Scientific Advisory Boards for Novartis, Roche,
Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics and Alkermes.
Author details
1 Department of Public Health, Mental Health and Wellbeing Research
Group, Vrije Universiteit Brussel, Brussels, Belgium. 2 Cerebra Network
for Neurodevelopmental Disorders, University of Birmingham, Birmingham,
UK. 3 Emma Children’s Hospital, Amsterdam University Medical Center,
Amsterdam, The Netherlands. 4 TAND Expert Centre, ‘s Heeren Loo, Hoofd‑
dorp, The Netherlands. 5 Division of Child & Adolescent Psychiatry, Centre
for Autism Research in Africa (CARA), University of Cape Town, Cape Town,
South Africa. 6 Department of Paediatric Neurology, University Hospitals
Leuven, Leuven, Belgium. 7 Department of Development and Regeneration,
KU Leuven, Leuven, Belgium. 8 Department of Pediatrics, Division of Neurol‑
ogy, Cincinnati Children’s Hospital Medical Center/University of Cincinnati
College of Medicine, Cincinnati, OH, USA. 9 Department of Neurology,
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 10 Argentine
Program for Children, Adolescents and Adults with Autism Spectrum Disorders
(PANAACEA), Buenos Aires, Argentina. 11 Department of Neurology, Harvard
Medical School & Boston Children’s Hospital, Boston, MA, USA. 12 TSC Canada,
Mississauga, Ontario, Canada. 13 Stellenbosch University, Stellenbosch, South
Africa. 14 Department of Pediatrics, University of Tennessee Health Sciences
Center, Memphis, TN, USA. 15 Le Bonheur Children’s Hospital and Boling Center
for Developmental Disabilities, Memphis, TN, USA. 16 TSC Alliance, Silver Spring,
MD, USA. 17 St. George’s University of London, London, UK. 18 The Royal Sussex
County Hospital, Brighton, UK. 19 TSC Clinic Cincinnati Children’s Hospital Medi‑
cal Center, Cincinnati, OH, USA. 20 Department of Pediatrics, Clinical Pediatrics
and Neurology, University of Cincinnati College of Medicine, Cincinnati, OH,
USA. 21 Department of Neurology, Translational Neuroscience Center, Boston
Children’s Hospital, Harvard Medical School, Boston, MA, USA. 22 Belgian TSC
Association (Be‑TSC), Mortsel, Belgium. 23 Tuberous Sclerosis Alliance India,
Mumbai, India. 24 Japanese Society of Tuberous Sclerosis Complex, Tokyo,
Japan. 25 Child and Adolescent Psychiatry, University Medical Center Göttin‑
gen, Georg‑August University, Göttingen, Germany. 26 Department of Pediat‑
rics, Pediatric Neurology Unit, Antwerp University Hospital, Edegem, Belgium.
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... El término TAND (sigla en inglés de TSC-associated neuropsychiatric disorders) fue introducido en la literatura científica en 2013 y rápidamente aceptado como un concepto "paraguas" para incluir un amplio rango de manifestaciones neuropsiquiátricas interrelacionadas, que incluyen dificultades y trastornos del comportamiento (hiperactividad, impulsividad, agresividad, trastornos del sueño), psiquiátricas (trastorno del espectro del autismo, trastorno por déficit atencional con hiperactividad, trastorno de ansiedad, depresión), intelectuales (discapacidad intelectual), académicas (trastornos del aprendizaje de la lectura, escritura y/o del razonamiento lógico-matemático), neuropsicológicas (déficit atencionales, de memoria, de funciones ejecutivas) y psicosociales (baja autoestima, estrés familiar excesivo, estigma social) 1,7 . ...
Article
Tuberous sclerosis complex is an autosomal dominant genetic multisystemic disorder caused primarily by mutations in one of the two tumor suppressor genes TSC1 or TSC2, resulting in increased activation of the mTOR pathway. Regarding clinical manifestations, a wide range of phenotypic variability exists, with symptoms constellations that may differ in affected organs (brain, skin, heart, eyes, kidneys, lungs), age of presentation and severity, but usually with great impact in biopsychosocial aspects of health and in quality of life. Main clinical neurological features are epilepsy (frequently, antiepileptic drug-resistant epilepsy), neuropsychiatric disorders, and subependymal giant cell astrocytomas. Recently, many therapeutic strategies have developed, including preventive treatment of epilepsy, new options for treatment of epilepsy as cannabidiol, mTOR inhibitors, ketogenic diet, and a more precise epilepsy surgery. Subependymal giant cell astrocytomas may require surgical procedures or mTOR inhibitors treatment. mTOR inhibitors may also be useful for other comorbidities. To improve quality of life of patients with tuberous sclerosis complex, it is essential to be able to deliver an integrated approach by specialized multidisciplinary teams, coordinated with primary care physicians and health professionals, that include access to treatments, attention of psychosocial aspects, and an adequate health care transition from pediatric to adult care.
Article
Full-text available
Background Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder, is associated with a wide range of TSC-Associated Neuropsychiatric Disorders ( TAND). Individuals have apparently unique TAND profiles, challenging diagnosis, psycho-education, and intervention planning. We proposed that identification of natural TAND clusters could lead to personalized identification and treatment of TAND. Two small-scale studies showed cluster and factor analysis could identify clinically meaningful natural TAND clusters. Here we set out to identify definitive natural TAND clusters in a large, international dataset. Method Cross-sectional, anonymized TAND Checklist data of 453 individuals with TSC were collected from six international sites. Data-driven methods were used to identify natural TAND clusters. Mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. Statistical robustness of clusters was evaluated with 1000-fold bootstrapping, and internal consistency calculated with Cronbach’s alpha. Results Ward’s method rendered seven natural TAND clusters with good robustness on bootstrapping. Cluster analysis showed significant convergence with an exploratory factor analysis solution, and, with the exception of one cluster, internal consistency of the emerging clusters was good to excellent. Clusters showed good clinical face validity. Conclusions Our findings identified a data-driven set of natural TAND clusters from within highly variable TAND Checklist data. The seven natural TAND clusters could be used to train families and professionals and to develop tailored approaches to identification and treatment of TAND. Natural TAND clusters may also have differential aetiological underpinnings and responses to molecular and other treatments.
Article
Full-text available
Background Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods Chairs and working group co-chairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference July 25-26 in Dallas, TX, USA. Prior to the meeting, working group co-chairs worked with group members via email and telephone to a) review TSC literature since the 2013 publication, b) confirm or amend prior recommendations, and c) provide new recommendations as required. Results Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for EEG abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals. Conclusions Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
Article
Full-text available
Abstract Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC. Methods We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders. Results We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18–61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p
Article
Full-text available
Background: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. Methods: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. Results: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. Conclusions: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters.
Article
Full-text available
Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population.
Article
Full-text available
Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Article
Full-text available
Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Article
Full-text available
Background: Research in rare genetic syndromes associated with ASD is often hampered by the wide geographic distribution of families and the presence of medical comorbidities, such as epilepsy, that may preclude travel to clinical sites. These challenges can limit the sample size and generalizability of the cohorts included in both natural history studies and clinical trials. Tuberous sclerosis complex (TSC) is a rare genetic syndrome that confers an elevated risk for autism spectrum disorder (ASD), with social communication delays identified in this population as early as 12 months of age. Early identification of risk necessitates parallel testing of early intervention, prompting the first randomized controlled clinical trial of behavioral intervention for infants with TSC (NCT03422367). However, considerable early recruitment challenges have mandated the systematic identification of enrollment barriers followed by modification of the study design to address these barriers. Methods: Caregivers were interviewed regarding barriers to enrollment (phase 1). Adaptations to the intervention were made to address these barriers (phase 2). Outcomes based on this modification to the study design were defined by enrollment rate and participant demographics. Results: Qualitative reports from caregivers indicated that distance and time were the primary barriers to clinical trial enrollment. The intervention was then modified to a remote model, with at-home, parent-delivered intervention, and weekly video conferencing with interventionists at the study sites. Enrollment increased 10-fold (from 3 to 30 participants) within 1 year and included a more diverse and clinically representative cohort of infants. Conclusion: The design and implementation of more scalable methods to disseminate research remotely can substantially improve access to clinical trials in rare neurodevelopmental disorders. The lessons learned from this trial can serve as a model for future studies not only in rare conditions, but in other populations that lack adequate access, such as families with limited financial or clinical resources. Continued efforts will further refine delivery methods to enhance efficiency and ease of these delivery systems for families.
Article
Full-text available
Objective: This review will summarize current knowledge on the burden of illness (BOI) in tuberous sclerosis complex (TSC), a multisystem genetic disorder manifesting with hamartomas throughout the body, including mainly the kidneys, brain, skin, eyes, heart, and lungs. Methods: We performed a systematic analysis of the available literature on BOI in TSC according to the PRISMA guidelines. All studies irrespective of participant age that reported on individual and societal measures of disease burden (e.g. health care resource use, costs, quality of life) were included. Results: We identified 33 studies reporting BOI in TSC patients. Most studies (21) reported health care resource use, while 14 studies reported quality of life and 10 studies mentioned costs associated with TSC. Only eight research papers reported caregiver BOI. Substantial BOI occurs from most manifestations of the disorder, particularly from pharmacoresistant epilepsy, neuropsychiatric, renal and skin manifestations. While less frequent, pulmonary complications also lead to a high individual BOI. The range for the mean annual direct costs varied widely between 424 and 98,008 International Dollar purchasing power parities (PPP-$). Brain surgery, end-stage renal disease with dialysis, and pulmonary complications all incur particularly high costs. There is a dearth of information regarding indirect costs in TSC. Mortality overall is increased compared to general population; and most TSC related deaths occur as a result of complications from seizures as well as renal complications. Long term studies report mortality between 4.8 and 8.3% for a follow-up of 8 to 17.4 years. Conclusions: TSC patients and their caregivers have a high burden of illness, and TSC patients incur high costs in health care systems. At the same time, the provision of inadequate treatment that does not adhere to published guidelines is common and centralized TSC care is received by no more than half of individuals who need it, especially adults. Further studies focusing on the cost effectiveness and BOI outcomes of coordinated TSC care as well as of new treatment options such as mTOR inhibitors are necessary.
Article
Tuberous sclerosis complex (TSC) is a rare genetic syndrome that confers risk for neurodevelopmental disorders, including autism spectrum disorder and intellectual disability. Delays in social communication and early cognitive abilities are observable as early as 9 months of age in children with TSC; however, there have been no studies of early behavioral intervention in TSC. We conducted a pilot study of an evidence-based, parent-mediated behavioral intervention focused on improving early social communication and play skills in 5 children with TSC (aged 1–3 years). Participants showed maintenance and sometimes gains in developmental abilities, relative to peers, following intervention. Parents generally found the intervention to be helpful and were able to administer the intervention with fidelity. Preliminary results demonstrate initial feasibility of an early play-based, parent-mediated intervention and support the need for a large-scale, randomized clinical trial in TSC.