Figure 2 shows a conceptual representation of the evidence-informed consensus clinical recommendations. At the heart of the recommendations are ten core principles to be used by clinicians and families as an overall guide to the identification and treatment of TAND. This is surrounded by cluster-specific recommendations for each of the seven natural TAND clusters. Around all these recommendations, the wraparound psychosocial cluster recommendations were placed to show how these “wrap around” all the core principles and cluster recommendations.

Fig. 2

Visual summary of the consensus recommendations for TAND. Recommendations include ten core principles (outlined in Table 2), seven sets of cluster-specific recommendations (outlined in Tables 3, 4, 5, 6, 7, 8 and 9), and wraparound psychosocial recommendations (outlined in Table 10)

Core principles for the identification and treatment of TAND

The ten core principles for identification and treatment of TAND are shown in Table 2 and are proposed as a framework to approach any individual with TSC, regardless of their age, sex, genotype (e.g., TSC1 or TSC2), or TAND profile. It recognizes that everyone with TSC is at risk of TAND manifestations (#1) and that it is therefore important to perform lifelong monitoring for the emergence of TAND difficulties (#2) with a minimum of annual screening (#3). The core principles recommend early identification and early intervention (#4) rather than to use a “watch-and-wait” strategy. The consensus panel proposes a cluster-based profiling and identification of needs, but acknowledges that clusters cluster together and that identification of needs in one cluster should also alert caregivers and clinical teams to explore other clusters (#5). In the context of a multi-system condition, core principle #6 points to the importance of the relationship between physical health manifestations and TAND manifestations. Core principle #7 underlines the importance of working with caregivers as lived experts in TSC. Recognizing the very limited traditional “evidence base” in TAND, caregivers, and family communities have valuable contributions to make both in identification and in intervention for TAND. Principle #8 serves as a reminder that TAND difficulties require a “whole-system” understanding to guide an intervention plan. This means that biological, psychological, and social (“bio-psycho-social”) aspects should be considered to understand the needs and to provide interventions and support. By implication, this process requires contributions from many professional groups and disciplines and is not just about finding a “medication” to solve a problem. In spite of the limited evidence base from the scientific literature specifically on TAND, principle #9 recommends the need to be informed by whatever relevant evidence may exist and to guard against approaches known to have evidence of harm. The final principle (#10) is a reminder that the goal of “intervention” and support to individuals with TSC and their caregivers is not merely to reduce symptoms or difficulties, but to help everyone living with TSC achieve an optimal quality of life as individuals and as families and to facilitate their active participation in all aspects of society throughout their journey with TSC and TAND.

Table 2 The ten core principles for the identification and treatment of TSC-associated neuropsychiatric disorders (TAND)Cluster-specific recommendations

Consensus recommendations for the seven natural TAND clusters and the wraparound psychososocial cluster are presented in the text below and in Tables 3, 4, 5, 6, 7, 8, 9 and 10.

Autism-like cluster

The autism-like cluster recommendations are shown in Table 3. TSC is associated with very high rates of social-communication difficulties and a significant proportion of individuals with TSC meet the criteria for autism as defined in the DSM-5 or ICD-11 [16, 28,29,30,31]. However, these difficulties are often identified or diagnosed late, and many children and families miss out on opportunities to access some of the growing number of evidence-based interventions and support programs developed specifically for autism [4]. Similarly, adults with TSC who have social-communication difficulties or autism rarely receive interventional support.

Table 3 Autism-like cluster recommendations

For these reasons, the consensus panel recommended lifelong monitoring of all individuals for manifestations in the autism-like cluster (AU1), from early in infancy and throughout adulthood (AU2). All individuals who show difficulties with autism-like cluster manifestations should be referred for a formal clinical evaluation for communication disorders and autism/autism spectrum disorder (AU3). In the absence of TSC-specific evidence, the consensus panel recommended that the autism literature on children and adults in the general population (i.e., for those with autism without TSC) may be relevant to the TSC community (AU4). For this reason, young children with autism and TSC may benefit from naturalistic developmental behavioral interventions (NDBI) [32, 33], the group of autism interventions with the strongest evidence base at present (AU5). Similarly, adults with TSC and autism-like cluster manifestations may benefit from autism interventions such as social skills training (AU6) [33]. Recognizing the very high rates of co-occurring physical health, neurodevelopmental, and mental health problems in autism in the general population [33], as well as the common co-occurrence of other TAND clusters with the autism-like cluster [18], the panel recommended lifelong monitoring for the presence of co-occurring conditions, followed by appropriate evidence-informed treatments (AU7). Even though autism and the autism-like cluster have been the most extensively examined in TSC research [27], much further research is recommended, particularly in relation to non-pharmacological interventions for difficulties in this cluster (AU8).

Dysregulated behavior cluster

The dysregulated behavior cluster recommendations are shown in Table 4. Difficulties with aggression, temper tantrums, and/or self-injurious behaviors represent some of the greatest concerns and burdens to families who live with TSC [29]. These behaviors are therefore a common reason for referral to specialist services. However, there may be many different reasons for or “pathways” to dysregulated behaviors in TSC. For example, they may be driven by communication difficulties, impulsivity, anxiety, sensory sensitivities, demand avoidance, cognitive inflexibility, trauma, and/or pain [34,35,36,37]. Dysregulated behaviors may also emerge as a result of the physical manifestations of TSC, such as growing SEGA, seizures, or as an adverse effect of medications. For this reason, there is no single intervention approach to this cluster of difficulties, and, equally, no single or simple medication that should be used to “manage” these behaviors. There are also no behavioral treatment studies for dysregulated behavior specifically in people with TSC. However, there is moderate support for real interventions for individuals with intellectual disabilities without TSC, which should inform practice [38]. Non-pharmacological/behavioral interventions may include speech/language work to support communication difficulties, cognitive-behavioral work to support anxiety behaviors and cognitive inflexibility, a range of sensory strategies to support the sensory sensitivities that may trigger dysregulated behaviors, and a range of environmental strategies such as visual schedules to increase predictability and support transitions during daily activities [34,35,36,37,38].

Table 4 Dysregulated behavior cluster recommendations

For these reasons, the consensus panel stated that dysregulated behaviors are common, have a major impact on families, and should be investigated in a systematic way (DB1). Given the many possible underlying meanings or functions of behaviors, a careful and systematic functional analysis of behavior should be conducted to generate an understanding of the problem behavior (DB2) [39]. Another important step towards a good understanding is to conduct an evaluation of the intellectual and neuropsychological profile of the individual with TSC (DB3). To ensure rapid identification of any underlying biological cause of dysregulated behaviors, urgent physical examination is recommended for sudden onset and/or rapidly changing or unexpected dysregulated behaviors (DB4). Once the evaluation has been completed, biological causes identified and treated, and a good understanding of the pathways to the dysregulated behavior has been identified, non-pharmacological strategies are recommended as first-line treatment (DB5). Medications should only be used for dysregulated behaviors after a careful and systematic evaluation and always alongside a non-pharmacological intervention plan (DB6). The consensus panel also recognized the need to generate an evidence base particularly for non-pharmacological interventions for dysregulated behaviors in individuals with TSC (DB7).

Eat/sleep cluster

The eat/sleep cluster recommendations are shown in Table 5 with separate recommendations for eating- and sleep-related difficulties. Eating difficulties in TSC are a highly under-researched domain, but the consensus panel recognized that they do occur and may be associated with a range of TAND and/or physical manifestations (ES1). Where eating difficulties are reported, a comprehensive evaluation should be performed to consider the range of potential contributors (e.g., picky eating, autism-related restricted eating, mouth ulcers or anorexia associated with medications, physical ill-health, or pain) (ES2). Recognizing the wide range of developmental, intellectual, and communication levels in TSC, intervention plans for eating should be adapted to the individual needs and profile of each person with TSC. The consensus panel stated that there are no dietary supplements or restricted/special diets with an evidence base in TSC to improve any TAND manifestations (ES3). The ketogenic diet is a well-known approach used for refractory seizures in TSC, but the evidence that it has a direct impact on TAND is mixed [40].

Table 5 Eat/sleep cluster recommendations

Sleep difficulties are very common across all ages in TSC [4, 41], but there is a complex “bidirectional” association between sleep and other manifestations. For example, sleep difficulties may contribute to neuropsychological difficulties (e.g., in memory or attention), dysregulated behaviors (e.g., increased aggression or temper tantrums), mood problems, or seizures (acting to reduce seizure thresholds or acting as trigger events). Conversely, sleep difficulties may result from other TAND manifestations (e.g., autism-related rigid sleep routines, mood/anxiety-driven insomnia, or early morning wakening), neurological manifestations (e.g., waking from a nocturnal seizure), or result from adverse effects of medications. Sleep difficulties may also be maintained by a behavioral model of reinforcement, such as access to electronic devices or caregiver contact upon waking, or an inadvertent mutual reinforcement cycle including caregivers (e.g., co-sleeping in the caregivers’ bed to help them settle). Pathways to sleep difficulties are complex, and assessment strategies therefore need to be set up to understand each individual’s pathways to their sleep difficulties, in order to ensure appropriate management.

For these reasons, the consensus panel emphasized that sleep difficulties should be monitored regularly regardless of the age, sex, and genotype (ES4) of individuals and that sleep difficulties may be a “cause” and/or a “consequence” of TAND or other neurological manifestations (ES5). Clinicians and caregivers should therefore perform careful examinations to first identify and treat biological contributors to sleep, such as underlying health conditions and behavioral markers of pain (ES6). Next, psychiatric contributors to sleep should be examined and treated (e.g., early morning wakening as part of a depressive disorder or disturbed sleep in the context of an anxiety disorder). Only once these have been identified and treated (or excluded), should other sleep management strategies be explored. Non-pharmacological strategies should always be used first (e.g., sleep education, sleep hygiene) before pharmacological strategies (e.g., melatonin or similar medications) are considered (ES7). Given the very limited evidence base in this cluster, the consensus panel recommended targeted research on eating and sleeping difficulties in TSC (ES8).

Mood/anxiety cluster

The mood/anxiety cluster consensus recommendations are shown in Table 6. The rates of mood and anxiety symptoms and disorders are very high in TSC, often arising in adolescence or adulthood. Difficulties in this cluster are often identified late or not at all. In those with developmental or intellectual disabilities, the identification of mood and anxiety difficulties may be even more difficult. Even though there is no evidence base within TSC for the treatment of depressive and anxiety disorders, there is an encouraging evidence base in the general population that indicates the use and effectiveness of non-pharmacological and pharmacological strategies.

Table 6 Mood/anxiety cluster recommendations

For these reasons, the consensus panel recommended that all children and adults should be monitored for the emergence of mood and anxiety symptoms to ensure early detection and treatment (MA1). Particular efforts should be made to look for mood and anxiety symptoms in those with intellectual and other neurodevelopmental disabilities where manifestations of depressed mood or anxiety may be different (e.g., withdrawal from social interaction, loss of interest in previously enjoyed activities, anorexia, or increased dysregulated behaviors) (MA2). Mood and anxiety symptoms may be the consequence of underlying physical health problems or their treatments (e.g., seizures and anti-seizure medications, renal failure, or chronic pain), and these may require specific management (MA3). Where mood and anxiety symptoms are identified, an appropriate diagnostic evaluation should be performed, and evidence-based non-pharmacological and pharmacological interventions as recommended in the general population should be used to treat mood and anxiety disorders (MA4). Given the heterogeneity in the individual physical health and TAND profiles of individuals with TSC, a personalized approach to management is recommended (MA5). In spite of the high rates of mood and anxiety disorders in TSC, the research evidence base is very limited, and further research, particularly interventional research, was recommended (MA6).

Neuropsychological cluster

The neuropsychological cluster consensus clinical recommendations are shown in Table 7. About half of the individuals with TSC have normal-range intellectual ability (with IQ > 80) and 40–50% have intellectual disabilities. However, the individual profiles of strengths and weaknesses are highly variable between individuals and are often very uneven within individuals regardless of their “overall” intellectual ability [4, 15, 29, 42]. Intellectual ability is a very strong correlate of many TAND manifestations, and uneven intellectual profiles can be associated with many functional impairments. Even in people with above-average and high intellectual abilities, the rates of specific neuropsychological deficits (e.g., in attentional, memory, or executive skills) are very high and can be associated with significant challenges in daily life (e.g., in school, relationships, or the workplace) [43, 44]. This is even more likely to be the case for those with TSC known to have neurodevelopmental disorders such as autism, attention deficit hyperactivity disorder (ADHD), or learning disorders. Understanding the neuropsychological profile of an individual with TSC can help to understand current difficulties and to predict future ones. Performing these evaluations in preparation for transitions in school, in preparation for post-secondary training or for the workplace, and implementing neuropsychological intervention plans, can be of significant value.

Table 7 Neuropsychological cluster recommendations

For these reasons, the consensus panel recommended that all individuals with TSC should have a comprehensive assessment of their intellectual abilities (NP1) and should be monitored with annual screening for the emergence of neuropsychological deficits (NP2). The recommendations highlighted the fact that specific neuropsychological deficits may have an impact in many ways, including mood and anxiety difficulties (e.g., feeling anxious or easily overwhelmed), having dysregulated behaviors when task demands become too much (e.g., when expected to switch flexibly between tasks), or on their scholastic skills (e.g., in reading, writing, or mathematics) (NP3). Individuals with known neurodevelopmental disorders should receive a detailed evaluation of their profile of neuropsychological strengths and weaknesses and not only be screened for such deficits (NP4). Importantly, the consensus panel recommended that non-pharmacological coaching and training strategies should be used to strengthen areas of neuropsychological deficits (NP5) and that evidence of neuropsychological deficits is likely to require accommodations and specific support in educational or occupational settings (NP6).

Overactive/impulsive cluster

The overactive/impulsive cluster recommendations are shown in Table 8. Overactive, impulsive, and restless behaviors are very common in TSC. Even though the manifestations are typically lower in adults than children, they are seen across ages, sex, and different genotypes [14, 29]. There are many possible reasons why people with TSC have difficulties in this cluster, including physical health, developmental, or environmental reasons. However, a significant proportion of people with difficulties in this cluster may meet the criteria for ADHD and may therefore benefit from the evidence-based treatment strategies for ADHD as recommended in the general population [45], even when they may have co-occurring seizures [46], autism [33], and/or intellectual disability [47, 48].

Table 8 Overactive/impulsive cluster recommendations

For these reasons, the consensus panel recommended ongoing screening for difficulties in this cluster and to proceed to appropriate next-step evaluations when difficulties are identified (OI1). All individuals who have difficulties in this cluster should be considered for a diagnostic assessment for ADHD (OI2) and, if diagnosed, be treated using the evidence-based approaches as recommended in the general population (OI3). When ADHD manifestations are moderate-to-severe, treatment with methylphenidate or other stimulant medications should be considered alongside non-pharmacological strategies to support the individual (OI4). Even when ADHD is accompanied by epilepsy, intellectual disability, autism, or other physical or TAND manifestations, the ADHD symptoms may respond appropriately to pharmacological treatments (OI5). The consensus panel also recommended further research to understanding pathways to overactive and impulsive behaviors and to generate an evidence base for intervention strategies (pharmacological and non-pharmacological) for these manifestations in TSC (OI6).

Scholastic cluster

The scholastic cluster recommendations are shown in Table 9. Scholastic difficulties are very common in TSC regardless of the intellectual abilities of individuals with TSC, with rates around 60% [15]. There are often early risk markers of later scholastic difficulties such as the delayed onset of language development, difficulties in social communication, or other developmental milestones [49,50,51]. The majority of school-aged children with TSC are therefore likely to benefit from additional support and/or a personalized approach to their education.

Table 9 Scholastic cluster recommendations

For these reasons, the consensus panel recommended early and ongoing screening for scholastic cluster difficulties followed by appropriate action when concerns are identified (S1). The panel highlighted that delays in early developmental milestones may be markers of future scholastic difficulties (S2). All children with TSC should be considered for an individual educational plan (IEP/IEDP) to support their individual profile of learning needs (S3). There is no “one-size-fits-all” in education provision for children with TSC, and the goal should therefore be to match the comprehensive needs of each child with the most appropriate educational environment (S4). Acknowledging that educational environments and supports may vary significantly across the globe, the panel recommended that in all educational settings, high-quality teaching strategies, response-to-intervention (RTI) approaches, and appropriate accommodations (e.g., differentiated reading material, seats close to the educator, extra time, quite spaces, chunked assignments) should be provided [52, 53] (S5). Educators should monitor the overall TAND profile of each child with TSC and consider how it may affect the child’s ability to access education (S6). Planning for educational transitions through each stage of schooling and beyond secondary education was also recommended (S7).

Wraparound psychosocial cluster

The wraparound psychosocial cluster recommendations are shown in Table 10. The psychosocial health and wellbeing of individuals and families who live with TSC is a priority area, yet very little research has been conducted in this domain, and very little is typically done to evaluate and support the psychosocial needs of families [54,55,56,57,58].

Table 10 Wraparound psychosocial cluster recommendations

For this reason, the consensus panel recommended monitoring of the psychosocial health and wellbeing of all individuals with TSC (PS1) and of all their family members (PS2), using screening (e.g., with the TAND-SQ Checklist), observation, family reports, or other standardized instruments. Based on their psychosocial needs, families should be provided with integrated and well-coordinated care (PS3). This should include practical support as well as psychosocial interventions (e.g., psychological therapies) as required (PS4). The overall focus should be on “family quality of life” by helping individuals and families identify their goals towards, for example, social activities and active participation (PS5). TSC often has a major impact on the employment and professional lives of individuals with TSC and their families. This should therefore also be a specific focus of psychosocial support provided (PS6). The consensus panel recognized that families and caregivers are paramount to the wellbeing of individuals with TSC and of the whole family. It is therefore of fundamental importance to “care for caregivers” by monitoring caregiver wellbeing, dedicating time in consultations to family and caregiver wellbeing, and generating evidence of interventional approaches that could strengthen caregiver wellbeing (PS7).