Mammalian Target of Rapamycin Inhibitor Levels Decrease Under Cenobamate Treatment.

Background: Everolimus therapy has been approved in Tuberous Sclerosis Complex (TSC), for drug-resistant epilepsy as adjunctive therapy. A novel anti-seizure medication is cenobamate, which was approved for adults as adjunctive treatment for focal-onset seizures in drug-resistant epilepsy and is now commonly used in patients with TSC. Drug-drug interactions between cenobamate and mammalian target of rapamycin (mTORi) have not been prospectively evaluated, even though these agents are frequently administered together.

Impact of seizure onset zone and intracranial electroencephalography ictal characteristics on epilepsy surgery outcomes in tuberous sclerosis complex.

Ninety percent of tuberous sclerosis complex (TSC) patients have seizures, with ∼50 % developing drug refractory epilepsy. Surgical intervention aims to remove the seizure onset zone (SOZ). This retrospective study investigated the relationship of SOZ size, ictal pattern, and extent of resection with surgical outcomes.

Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior.

Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature.

Abnormality of Early White Matter Development in Tuberous Sclerosis Complex and Autism Spectrum Disorder: Longitudinal Analysis of Diffusion Tensor Imaging Measures.

Abnormalities in white matter development may influence development of autism spectrum disorder in tuberous sclerosis complex (TSC). Our goals for this study were as follows: (1) use data from a longitudinal neuroimaging study of tuberous sclerosis complex (TACERN) to develop optimized linear mixed effects models for analyzing longitudinal, repeated diffusion tensor imaging metrics (fractional anisotropy, mean diffusivity) pertaining to select white matter tracts, in relation to positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months, and (2) perform an exploratory analysis using optimized models applied to all white matter tracts from these data. Eligible participants (3-12 months) underwent brain magnetic resonance imaging (MRI) at repeated time points from ages 3 to 36 months.

Common epilepsy variants from the general population are not associated with epilepsy among individuals with tuberous sclerosis complex.

Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC-associated epilepsy. Such knowledge is important to help uncover the underlying pathogenesis of epilepsy in TSC which is not fully understood, and critical as uncontrolled epilepsy is a major problem in this population.

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.

Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial.

Objective: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age.

Methods: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months.

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.

Tubers Affecting the Fusiform Face Area Are Associated with Autism Diagnosis.

Objective: Tuberous sclerosis complex (TSC) is associated with focal brain "tubers" and a high incidence of autism spectrum disorder (ASD). The location of brain tubers associated with autism may provide insight into the neuroanatomical substrate of ASD symptoms.

Methods: We delineated tuber locations for 115 TSC participants with ASD (n = 31) and without ASD (n = 84) from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network.

Comparison of outcomes after stereoelectroencephalography and subdural grid monitoring in pediatric tuberous sclerosis complex.

Objective: Patients with tuberous sclerosis complex (TSC) epilepsy present with unique clinical challenges such as early seizure onset and high rates of intractability and multifocality. Although there are numerous studies about the safety and efficacy of stereoelectroencephalography (SEEG), this topic has not been studied in TSC patients who have distinct epilepsy profiles. The authors investigated subdural grid (SDG) and SEEG monitoring to determine whether these procedures lead to similar seizure and safety outcomes and to identify features unique to this pediatric population.

Limited utility of structural MRI to identify the epileptogenic zone in young children with tuberous sclerosis.

Background And Purpose: The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC.

Methods: We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12 months or more follow-up.

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.

Prevalence of thoracoabdominal imaging findings in tuberous sclerosis complex.

Background: Tuberous sclerosis complex (TSC) results in neurodevelopmental phenotypes, benign tumors, and cysts throughout the body. Recent studies show numerous rare findings in TSC. Guidelines suggest routine abdominal and chest imaging to monitor these thoracoabdominal findings, but imaging is not uniformly done across centers.

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.

Symptom rates and profile clustering in tuberous sclerosis complex-associated neuropsychiatric disorders (TAND).

Background: Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric difficulties, appropriately termed TSC-Associated Neuropsychiatric Disorders (TAND). The objectives of the study were to analyze the rates of TAND symptoms in a cohort of patients seen at the TSC Center of Excellence at Cincinnati Children's Hospital and to identify clinically meaningful profiles based on TAND symptoms.

Methods: Data from the TAND Checklist was obtained from participants seen at the TSC Center of Excellence at Cincinnati Children's Hospital Medical Center from June 2015 to August 2018.

Profile of Autism Spectrum Disorder in Tuberous Sclerosis Complex: Results from a Longitudinal, Prospective, Multisite Study.

Objective: Tuberous sclerosis complex (TSC) is highly associated with autism spectrum disorder (ASD). Objectives of the study were to characterize autistic features in young children with TSC.

Methods: Participants included 138 children followed from ages 3 to 36 months with TSC from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study aimed at understanding the underlying mechanisms of ASD in TSC.

Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations.

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.

Epilepsy Is Heterogeneous in Early-Life Tuberous Sclerosis Complex.

Background: Epilepsy in tuberous sclerosis complex (TSC) typically presents with early onset, multiple seizure types, and intractability. However, variability is observed among individuals. Here, detailed individual data on seizure characteristics collected prospectively during early life were used to define epilepsy profiles in this population.

Diabetes in Individuals With Tuberous Sclerosis Complex Treated With mTOR Inhibitors.

Background: Tuberous sclerosis complex (TSC) is a genetic disorder that is manifested in multiple body systems. A mammalian target of rapamycin (mTOR) inhibitor (mTORi), either everolimus or sirolimus, is now routinely prescribed for multiple clinical manifestations of TSC, including subependymal giant cell astrocytoma and epilepsy. These medications are generally well tolerated.

Frequency, Progression, and Current Management: Report of 16 New Cases of Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex and Comparison With Previous Reports.

Tuberous sclerosis complex (TSC) is a genetic condition that causes benign tumors to grow in multiple organ systems. Nonfunctional pancreatic neuroendocrine tumors (PNETs) are a rare clinical feature of TSC with no specific guidelines outlined for clinical management at this time. Our purpose is to calculate the frequency of nonfunctional PNETs as well as characterize the presentation, current clinical management, and assess the impact of systemic mammalian target of rapamycin (mTOR) on nonfunctional PNETs in TSC.

mTOR Inhibitor Therapy for Tuberous Sclerosis Complex: Longitudinal Study of Muscle Mass Determined by Abdominal Cross-sectional Imaging with CT and MRI.

Purpose: To determine the effect of chronic mammalian target of rapamycin (mTOR) inhibition on skeletal muscle mass in patients with tuberous sclerosis complex (TSC).

Materials And Methods: In this retrospective study, patients with TSC who were taking mTOR inhibitors and who underwent at least two abdominal CT or MRI examinations between 2005 and 2017 were included ( = 24; 14 males; mean age, 14.5 years ± 7.

Tuber Locations Associated with Infantile Spasms Map to a Common Brain Network.

Objective: Approximately 50% of patients with tuberous sclerosis complex develop infantile spasms, a sudden onset epilepsy syndrome associated with poor neurological outcomes. An increased burden of tubers confers an elevated risk of infantile spasms, but it remains unknown whether some tuber locations confer higher risk than others. Here, we test whether tuber location and connectivity are associated with infantile spasms.