Family and developmental history of ADHD patients: a structured clinical routine interview identifies a significant profile.

Similar to other neurodevelopmental disorders, the diagnosis of attention-deficit hyperactivity disorder (ADHD) is based on clinical and psychosocial assessment. This assessment is performed in clinical practice using the clinical routine interview technique. Domains of the clinical routine interview are, among others, present symptoms, history of present illness and family and developmental history. Family and developmental history are important parts in the diagnostic process of ADHD. In contrast to the domains of present symptoms and history of present illness, there are currently no structured interviews or rating scales available to thoroughly assess family and developmental history in ADHD. The aim of the study was to assess the profile of operationalized data from a structured clinical routine interview addressing family and developmental history from ADHD patients and control participants. A structured interview to assess family and developmental history was derived from the guidelines used at different university hospitals for Child and Adolescent Psychiatry as well as from the descriptions in leading textbooks. Based on these guidelines and descriptions, the interview was an optimization of possible questions. Clinical data were obtained from parents of male patients who had the diagnosis of ADHD between the ages of 12-17 years (n = 44), and of healthy controls (n = 41). Non-metric data were operationalized into three categories, 0-normal behavior, 1-minor pathological behavior, 2-major pathological behavior. ADHD patients express a profile that significantly differs from control participants. Comparison of significant items with the empirical ADHD literature indicates strong agreement. Our findings support the importance and feasibility of the clinical routine interview in family and developmental history in the context of diagnosing ADHD.

[Rejection of closed placement in youth welfare: Two case reports and a discussion of needs and effectiveness]. / Ablehnung von Geschlossener Unterbringung in der Jugendhilfe.

Rejection of closed placement in youth welfare: Two case reports and a discussion of needs and effectiveness Abstract. Locked-door residential care in the custody of adolescents with severe behavioral problems has been a controversial subject in Germany for many decades. Sometimes the debate is held on an ideological level, sometimes it concerns the legal and ethical legitimacy of such actions, but it always is about providing the best care possible for severely disturbed adolescents with attachment disorder, severe conduct disorder, and psychosocial disintegration. Because of differing viewpoints on this issue, some German federal states have set up locked-door youth welfare institutions, whereas as others do not. Here, we present two stereotypical case constellations from the state of Saxony, where the absence of such locked-door residential institutions has served to shift the problem to clinics for child and adolescent psychiatry. Based on these case constellations, we discuss the present knowledge concerning the necessity and efficacy of these institutions. The discussion is followed by a critical reflection on constraint and autonomy in youth welfare.

[Neuropsychiatric manifestations in Tuberous Sclerosis Complex (TSC): diagnostic guidelines, TAND concept and therapy with mTOR inhibitors]. / Neuropsychiatrische Manifestationen bei Tuberöser Sklerose (TSC): Diagnostische Leitlinien, TAND-Konzept und Therapie mit mTOR-Inhibitoren.

Neuropsychiatric manifestations in Tuberous Sclerosis Complex (TSC): diagnostic guidelines, TAND concept and therapy with mTOR inhibitors Abstract. Tuberous sclerosis complex (TSC), albeit a rare autosomal-dominant multisystem disease with an incidence of 1:6,000, is one of the most important monogenetic disorders in child and adolescent psychiatry. In up to 90 % of patients, neurological disorders such as epilepsy and psychiatric disorders such as autism spectrum disorder, ADHD, affective disorders, and intellectual disability are observed. In recent years, significant progress has been made in understanding the molecular mechanism as well as in the clinical diagnosis and treatment of the disease. Here, we review these recent developments. In the first part, we describe the need for psychiatric assessment and treatment of patients and analyse challenges in interdisciplinary work between child and adolescent psychiatry, child neurology, and other professional groups. In the second part, we introduce the concept of TSC-associated neuropsychiatric disorders (TAND), developed by the TSC Neuropsychiatry Panel as a guide to help clinical teams, families, and individuals with TSC via screening, assessment, and treatment of neuropsychiatric symptoms and disorders as well as with a novel screening instrument, the TAND Checklist. Finally, we report findings from recent clinical trials of mTOR-inhibitors to treat TAND. The paper includes the German translation of the TAND Checklist as an electronic supplement.

mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus.

Epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous sclerosis complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1 +/- and Tsc2 +/- mouse models by mammalian target of rapamycin (mTOR) inhibitors. However, at least 70 % of individuals with TSC also have epilepsy, known to complicate the severity and treatment responsiveness of the behavioural phenotype. No previous study has examined the impact of seizures on neurocognitive reversal by mTOR inhibitors. Adult Tsc2 +/- (Eker)-rats express social deficits similar to Tsc2 +/- mice, with additive social deficits from developmental status epilepticus (DSE). DSE was induced by intraperitoneal injection with kainic acid at post-natal days P7 and P14 (n = 12). The experimental group that modelled TSC pathology carried the Tsc2 +/- (Eker)-mutation and was challenged with DSE. The wild-type controls had not received DSE (n = 10). Four-month-old animals were analysed for social behaviour (T1), then treated three times during 1 week with 1 mg/kg everolimus and finally retested in the post-treatment behavioural analysis (T2). In the experimental group, both social interaction and social cognition were impaired at T1. After treatment at T2, behaviour in the experimental group was indistinguishable from controls. The mTOR inhibitor, everolimus, reversed social deficit behaviours in the Tsc2 haploinsufficiency plus DSE animal model to control levels.

Srgap3⁻/⁻ mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes.

Mutations in the SRGAP3 gene residing on chromosome 3p25 have previously been associated with intellectual disability. Genome-wide association studies have also revealed SRGAP3, together with genes from the same cellular network, as risk genes for schizophrenia. SRGAP3 regulates cytoskeletal dynamics through the RHO protein RAC1. RHO proteins are known to be involved in cytoskeletal reorganization during brain development to control processes such as synaptic plasticity. To elucidate the importance of SRGAP3 in brain development, we generated Srgap3-knockout mice. Ten percent of these mice developed a hydrocephalus and died before adulthood. Surviving mice showed various neuroanatomical changes, including enlarged lateral ventricles, white matter tracts, and dendritic spines together with molecular changes, including an increased basal activity of RAC1. Srgap3(-/-) mice additionally exhibited a complex behavioral phenotype. Behavioral studies revealed an impaired spontaneous alternation and social behavior, while long-term memory was unchanged. The animals also had tics. Lower locomotor activity was observed in male Srgap3(-/-) only. Srgap3(-/-) mice showed increased methylphenidate stimulation in males and an impaired prepulse inhibition in females. Together, the results show neurodevelopmental aberration in Srgap3(-/-) mice, with many of the observed phenotypes matching several schizophrenia-related intermediate phenotypes. Mutations of SRGAP3 may thus contribute to various neurodevelopmental disorders.

Meningitis in a pregnant woman caused by Streptococcus dysgalactiae subspecies equisimilis.

Infection of the central nervous system by streptococci is known to result in severe bacterial meningitis, however some strains have low pathogenic potential and affect the brain only in immunocompromised patients. Here we report the first case of an otherwise healthy non immunocompromised young adult woman who developed meningitis caused by Streptococcus dysgalactiae subspecies equisimilis. The patient was in the 17th week of her 3rd pregnancy. The course of the disease was quickly remittent under antibiotic treatment.

Family and developmental history of female versus male adolescents with ADHD: diagnosis-specific overlap, few gender/sex differences.

Background: Gender and sex differences in the development of children and adolescents are commonly found in the psychiatric examination. Family and developmental history is an important part of the clinical diagnostic interview, the basic examination technique. Attention-deficit/hyperactivity disorder (ADHD) is associated with diagnosis-specific markers in family and development history. However, it is unclear to what extent ADHD-specific signs and narratives differ between females and males. The aim of this study was to assess and to compare the family and developmental history profiles of female versus male adolescents with ADHD. Methods: Data were collected using the clinical diagnostic interview technique from parents of female and male patients diagnosed with ADHD (ICD-10 F90.0, F90.1 and F98.8) between the ages of 12 and 17 years (n = 92). The two groups were matched in pairs for sex, IQ and ICD-10 diagnosis (F90.0, F90.1 and F98.8). Interview data were operationalized in three categories: 0 - physiological marker, 1 - subclinical marker, 2 - clinical marker. The two groups were compared with two-way ANOVA. Results: Information about female in comparison to male adolescents were reported in the parental interview with few differences. Conclusion: Our study suggests that family and developmental history of the neurodevelopmental disorder ADHD is only poorly influenced by gender or sex.

Development and Feasibility of the Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ).

BACKGROUND: Tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) are often present but underidentified and undertreated in individuals with tuberous sclerosis complex (TSC). The clinician-completed TAND-Lifetime Checklist (TAND-L) was developed to address this identification and treatment gap. Stakeholder engagement identified the need for a TAND Checklist that can (1) be completed by caregivers or individuals with TSC and (2) quantify TAND difficulties. The aim of this study was to develop a self-report quantified TAND Checklist (TAND-SQ) and conduct feasibility and acceptability testing. METHODS: This aim was addressed in three phases: (1) development of the TAND-SQ Checklist, (2) feasibility and acceptability testing of the "near-final" TAND-SQ Checklist, and (3) preparation of the final TAND-SQ Checklist. Participants included 23 technical experts from the TAND consortium in all phases and 58 lived experts (caregivers and individuals with TSC) in phase 2. All participants completed a TAND-SQ Checklist and a checklist feedback form. RESULTS: Phase 1 additions to the TAND-SQ, when compared with the TAND-L, included four new items and a quantification rating. Phase 2 showed high ratings for the "near-final" TAND-SQ Checklist on comprehensiveness, clarity, ease of use, and overall acceptability. In phase 3, questions on strengths, strategies, and a TAND Cluster Profile were added. CONCLUSION: The TAND-SQ Checklist is presented here for use by individuals with TSC and their caregivers. The next steps as part of the TANDem project include internal and external validation of the checklist and linking of TAND Cluster Profiles generated from the checklist to evidence-informed consensus recommendations within a smartphone application.

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

BACKGROUND: Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific. METHODS: The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community. RESULTS: At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to "screen" for TAND at least annually, to "act" using appropriate next steps for evaluation and treatment, and to "repeat" the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families. CONCLUSIONS: The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a "TAND toolkit" of "what to seek" and "what to do" when difficulties are identified in TAND clusters.

The research landscape of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND)-a comprehensive scoping review.

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.

Empowering Families Through Technology: A Mobile-Health Project to Reduce the TAND Identification and Treatment Gap (TANDem).

Introduction: Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder with various TSC-Associated Neuropsychiatric Disorders (TAND) that significantly impact the mental health and wellbeing of individuals with TSC and their caregivers. TAND represents the number one concern to families worldwide, yet is highly under-identified and under-treated. The clinician-administered TAND-Checklist (Lifetime version, TAND-L) has improved identification of TAND in clinical settings. However, many individuals with TSC and their caregivers still have difficulty accessing suitable support for diagnosis and evidence-informed interventions. The TANDem study is a community-based participatory research project with a broad range of TSC stakeholders aimed at reducing the TAND identification and treatment gap. Objectives: Participatory research identified three priority next steps: 1) development and validation of a self-report, quantified version of the TAND Checklist (TAND-SQ) and building the TAND-SQ into a smartphone application, 2) generation of consensus clinical recommendations for the identification and treatment of TAND, to be incorporated as a TAND toolkit on the app, and 3) establishment of a global TAND consortium through networking, capacity-building and public engagement activities. Methods: TANDem is a four-year project, and includes 24 consortium members from 10 countries representing all World Health Organization regions. Collaborators represent five stakeholder groups (family representatives, technology experts, clinical experts, non-profit organisations and researchers). Here we outline the project study protocol in detail, describing the scientific rationale, the project aims and objectives, the methods involved in participant recruitment, multi-site and multi-phase data collection, data analysis, ethical considerations including informed consent, data protection, privacy and confidentiality considerations related to the European Union General Data Protection Regulation and the USA Health Insurance Portability and Accountability Act. The expected outcomes and potential impact on the TSC community, implementation and dissemination of results, as well as future scale-up and scale-out plans are also discussed. Conclusions: The TANDem project has the potential to transform the global TSC community by empowering families living with TSC through an easily accessible digital solution to allow them to document their own TAND needs linked to an evidence-informed toolkit to enhance personalised healthcare, and by providing healthcare professionals with consensus clinical recommendations to prevent, identify and manage TAND manifestations.

Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats.

There is a strong association between autism spectrum disorders (ASD), epilepsy and intellectual disability in humans, but the nature of these correlations is unclear. The monogenic disorder Tuberous Sclerosis Complex (TSC) has high rates of ASD, epilepsy and cognitive deficits. Here we used the Tsc2 (+/-) (Eker) rat model of TSC and an experimental epilepsy paradigm to study the causal effect of seizures on learning and memory and social behavior phenotypes. Status epilepticus was induced by kainic acid injection at P7 and P14 in wild-type and Tsc2 (+/-) rats. At the age of 3-6 months, adult rats were assessed in the open field, light/dark box, fear conditioning, Morris water maze, novel object recognition and social interaction tasks. Learning and memory was unimpaired in naïve Tsc2 (+/-) rats, and experimental epilepsy did not impair any aspects of learning and memory in either wild-type or Tsc2 (+/-) rats. In contrast, rearing in the open field, novel object exploration and social exploration was reduced in naïve Tsc2 (+/-) rats. Seizures induced anxiety and social evade, and reduced social exploration and social contact behavior in wild-type and Tsc2 (+/-) rats. Our study shows that Tsc2 haploinsufficiency and developmental status epilepticus in wild-type and Tsc2 (+/-) rats independently lead to autistic-like social deficit behaviors. The results suggest that the gene mutation may be sufficient to lead to some social deficits, and that seizures have a direct and additive effect to increase the likelihood and range of autistic-like behaviors.

Family and Developmental History of Individuals With Autism Spectrum Disorder: Importance of the Clinical Diagnostic Interview for Diagnosis in Adolescents. An Explorative Study.

Background: Diagnosis of autism spectrum disorder (ASD) can be made early in childhood, but also later in adolescence or adulthood. In the latter cases, concerns about an individual's behavior typically lead to consultation of a mental health professional (MHP). As part of the initial clinical examination by the MHP, a clinical diagnostic interview is performed, in order to obtain the patient's history, and may lead to the hypothesis of ASD. We were here interested to study family and developmental history as key parts of the patient's history. The aim of the study was to investigate empirical differences between adolescents with ASD and adolescent control persons in family and developmental history. Method: Clinical diagnostic interview items addressing family and developmental history were adopted from their regular use at several university hospitals and in leading textbooks. Parents of male adolescents with normal intelligence and an ASD diagnosis (n = 67) and parents of male adolescents without psychiatric diagnosis (n = 51) between the age of 12 and 17 years were investigated. Data were operationalized into three categories: 0 = normal behavior, 1 = minor pathological behavior, and 2 = major pathological behavior. Differences were analyzed by multiple t-test of two-way ANOVA. Results: Adolescents with ASD expressed a profile of items significantly differing from control persons. Comparison of significant items with the empirical ASD literature indicated robust accordance. Conclusions: Our findings support the importance and feasibility of the clinical diagnostic interview of family and developmental history for initiation of the diagnostic process of ASD in adolescents.

Involvement of mental health professionals in the treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND): results of a multinational European electronic survey.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare, genetic, multisystem disorder characterized by the growth of hamartomas in several organs, including the brain, kidneys, heart, eyes, and lungs. Even though over 90% of patients will have some form of TSC-associated neuropsychiatric disorder (TAND), there is an apparent lack of involvement of mental health professionals (MHPs) in the care of patients with TSC. The aim of this study was to determine the current level of TAND awareness in the TSC community and to identify possible barriers to effective multidisciplinary collaboration between MHPs and other healthcare providers (HCPs) in TAND management. METHODS: An electronic survey on current TSC and TAND management was conducted, targeting TSC caregivers/families, psychiatrists, neurologists, TSC specialists, and primary care physicians. RESULTS: The invitation to participate in the survey was emailed to 659 HCPs and was disseminated through social media channels of patient advocacy groups. The survey was open for 4 months, with 359 responses collected. The majority of participants were TSC caregivers/families (73.3% of all responses). Of the 96 HCPs who participated, most were neurologists (61.5%) or TSC specialists (28.1%). Only 6 psychiatrists and 4 primary care physicians participated. Approximately half of patients have never had a neuropsychiatric assessment, and it was their caregivers/families who initiated the discussion of TAND with their providers. Almost 70% of TSC caregivers/families believed that psychiatric treatment could improve their quality of life. However, 54% of patients had difficulty obtaining psychiatric assessment. In turn, only 21% of HCPs believed that psychiatric therapy would help and 74% were concerned that their patients would be stigmatized by psychiatric referral. CONCLUSIONS: This study focused on European healthcare systems suggests that current care for mental health issues in patients with TSC is inadequate, despite guideline recommendations for regular neuropsychiatric assessments. This appears to be due to a combination of gaps in diagnosis and surveillance, low frequency of psychiatric referrals, insufficient resources, and stigmatization of mental healthcare. There is a pressing need for further initiatives to study and address the mechanisms underlying the mental health treatment gap. The importance of MHP support must be recognized to optimize TSC management.