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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. Developmental and autism-specific assessments were administered, and a clinical diagnosis of ASD was determined for all participants at 36 months. Further analyses were performed on 117 participants with valid autism assessments based on nonverbal mental age greater than 15 months. RESULTS Prevalence of clinical diagnosis of ASD at 36 months was 25%. Nearly all autistic behaviors on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) were more prevalent in children diagnosed with ASD; however, autism-specific behaviors were also observed in children without ASD. Overall quality of social overtures, facial expressions, and abnormal repetitive interests and behaviors were characteristics most likely to distinguish children with ASD from those without an ASD diagnosis. Participants meeting ADOS-2 criteria but not a clinical ASD diagnosis exhibited intermediate developmental and ADOS-2 scores compared to individuals with and without ASD. INTERPRETATION ASD is highly prevalent in TSC, and many additional individuals with TSC exhibit a broad range of subthreshold autistic behaviors. Our findings reveal a broader autism phenotype that can be identified in young children with TSC, which provides opportunity for early targeted treatments. ANN NEUROL 2021;90:874-886.

To improve access to diagnostic evaluations for children younger than 3 years with concerns for possible autism spectrum disorder.A multidisciplinary "arena model" for children younger than 3 years was developed, tested, and implemented over an approximately 2-year period. Arena assessment teams comprised a developmental behavioral pediatrician (DBP), psychologist, and speech language pathologist (SLP). Quality improvement methods were used during the design phase, conducting Plan-Do-Study-Act (PDSA) cycles and collecting feedback from key stakeholders, and during implementation, plotting data on run charts to measure outcomes of the time to initial visit and time to diagnosis.Over the 9-month implementation period, 6 arena assessment teams were formed to provide 60 evaluation slots per month for children younger than 3 years. The time to first visit was reduced from a median of 122 days to 19 days, and the time to final diagnosis was reduced from 139 days to 14 days, maintaining these outcomes at35 and18 days, respectively, over a 2-year period. Total visits required decreased from 4 to 5 visits to just 2 visits, and the average assessment cost was reduced by $992 per patient. Feedback from both providers and families participating in this model was overwhelmingly positive.Access for young children referred for developmental assessments can be improved through an understanding of supply and demand and the development of creative and flexible care delivery models.

The Tuberous Sclerosis Complex Autism Center of Excellence Network (TACERN) is a 6-site collaborative conducting longitudinal research on infants with tuberous sclerosis complex (TSC), focused on identifying early biomarkers for autism spectrum disorder (ASD). A multidisciplinary research team that includes the specialties of psychology, neurology, pediatrics, medical genetics, and speech-language pathology, its members work together to conduct studies on neurological status, brain structure and function, neurodevelopmental phenotype, and behavioral challenges in this population. This article provides insights into the roles of the multidisciplinary multisite team and lessons learned from the collaboration, in terms of research as well as training of future researchers and clinicians. In addition, the authors detail the major findings to date, including those related to the identification and measurement of early symptoms of ASD, relationship between seizures and early development, and early biomarkers for epilepsy and developmental delay in infants and young children with TSC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background To determine if early epilepsy surgery mitigates detrimental effects of refractory epilepsy on development, we investigated surgical and neurodevelopmental outcomes in children with tuberous sclerosis complex who underwent surgery before age two years. Methods Prospective multicenter observational study of 160 children with tuberous sclerosis complex. Surgical outcome was determined for the seizure type targeted by surgery. We obtained Vineland Adaptive Behavior Scales, Second Edition (Vineland-II); Mullen Scales of Early Learning; and Preschool Language Scales, Fifth Edition, at age three, six, nine, 12, 18, 24, and 36 months. Surgical cases were compared with children without seizures, with controlled seizures, and with medically refractory seizures. Results Nineteen children underwent surgery (median age 17 months, range 3.7 to 21.3), and mean follow-up was 22.8 months (range 12 to 48). Surgical outcomes were favorable in 12 (63%, Engel I-II) and poor in seven (37%, Engel III-IV). Nine (47%) had new or ongoing seizures distinct from those surgically targeted. All children with seizures demonstrated longitudinal decline or attenuated gains in neurodevelopment, the surgical group scoring the lowest. Favorable surgical outcome was associated with increased Mullen Scales of Early Learning receptive and expressive language subscores compared with the medically refractory seizure group. A nonsignificant but consistent pattern of improvement with surgery was seen in all tested domains. Conclusions These pilot data show neurodevelopmental gains in some domains following epilepsy surgery. A properly powered, prospective multicenter observational study of early epilepsy surgery is needed, using both surgical and developmental outcome metrics.

After initially successful treatment of infantile spasms, the long-term cumulative risk of relapse approaches 50%, and there is no established protocol to mitigate this risk. Although vigabatrin may be an effective means to prevent relapse, there is little guidance as to ideal duration and dosage. Using a cohort of children with infantile spasms and tuberous sclerosis complex (TSC), we evaluated the potential association of post-response VGB treatment and the rate of infantile spasms relapse. Patients with infantile spasms and clinical response to vigabatrin were identified among a multicenter prospective observational cohort of children with TSC. For each patient we recorded dates of infantile spasms onset, response to vigabatrin, relapse (if any), and quantified duration and dosage of vigabatrin after response. Time to relapse as a function of vigabatrin exposure was evaluated using survival analyses. We identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3–22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1–9.6). Relapse occurred after VGB discontinuation in four patients, and during continued VGB treatment in the remaining eight cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01–28.4, P = 0.61), but weighted-average dosage was associated with marked reduction in relapse risk: Each 50 mg/kg/d increment in dosage was associated with 61% reduction in risk (HR 0.39, 95%CI 0.17 – 0.90, P = 0.026). This study suggests that the risk of infantile spasms relapse in TSC may be reduced by high-dose vigabatrin treatment.

Background Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to increase the risk, compared with TSC1. However, the effect of TSC2 pathogenic variants on early and specific domains of development hasn't been studied. Using an extensively phenotyped group, we aimed to characterize differences in early intellectual development between genotypes. Methods The study group (n = 92) included participants with TSC enrolled in a multicenter study involving genetic testing and detailed prospective phenotyping including the Mullen Scales of Early Learning, a validated measure of cognition, language, and motor development in babies and preschool children. Mean T-scores at 24 months for each Mullen Scales of Early Learning domain were calculated for children with, versus without, a TSC2 pathogenic variant. Multivariable linear regression models were used to compare the groups, adjusting for seizures. Results T-scores on every Mullen Scales of Early Learning domain were significantly worse in the TSC2 group. Below average composite scores were present in three-fourths of the TSC2 group, compared with one-fourth of those without TSC2. Having a TSC2 pathogenic variant was associated with lower composite Mullen Scales of Early Learning scores, even when corrected for seizures. Conclusions In a well-characterized patient population with standardized assessment of multiple aspects of development, we found that having a TSC2 pathogenic variant was associated with significantly lower Mullen Scales of Early Learning scores at age 24 months, independent of seizures. These data suggest that a baby with a TSC2 pathogenic variant is at high risk for significant developmental delays by 24 months.

Tuberous sclerosis complex (TSC) is a genetic disorder with high prevalence of associated autism spectrum disorder (ASD). Our primary objectives were to determine early predictors of autism risk to identify children with TSC in most need of early interventions. The Autism Observation Scale for Infants (AOSI) was evaluated as a measure of ASD-associated behaviors in infants with TSC at age 12 months and its ability to predict ASD at 24 months.Children ages 0 to 36 months with TSC were enrolled in the TSC Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study to identify biomarkers of ASD. The AOSI was administered at age 12 months and the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Autism Diagnostic Interview-Revised (ADI-R) at 24 months. Developmental functioning was assessed using the Mullen Scales of Early Learning. Children were classified as ASD or non-ASD according to the ADOS-2.Analysis included 79 children who had been administered the AOSI at 12 months and ADOS-2 and ADI-R at 24 months. The ASD group had a mean AOSI total score at 12 months significantly higher than the non-ASD group (11.8 ± 7.4 vs 6.3 ± 4.7; P 0.001). An AOSI total score cutoff of 13 provided a specificity of 0.89 to detect ASD with the ADOS-2. AOSI total score at 12 months was similarly associated with exceeding cutoff scores on the ADI-R.The AOSI is a useful clinical tool in determining which infants with TSC are at increased risk for developing ASD.

Objective Epilepsy is commonly seen in Tuberous Sclerosis Complex (TSC). The relationship between seizures and developmental outcomes has been reported, but few studies have examined this relationship in a prospective, longitudinal manner. The objective of the study was to evaluate the relationship between seizures and early development in TSC. Methods Analysis of 130 patients ages 0–36 months with TSC participating in the TSC Autism Center of Excellence Network, a large multicenter, prospective observational study evaluating biomarkers predictive of autism spectrum disorder (ASD), was performed. Infants were evaluated longitudinally with standardized evaluations, including cognitive, adaptive, and autism-specific measures. Seizure history was collected continuously throughout, including seizure type and frequency. Results Data were analyzed at 6, 12, 18, and 24 months of age. Patients without a history of seizures performed better on all developmental assessments at all time points compared to patients with a history of seizures and exhibited normal development at 24 months. Patients with a history of seizures not only performed worse, but developmental progress lagged behind the group without seizures. All patients with a history of infantile spasms performed worse on all developmental assessments at 12, 18, and 24 months. Higher seizure frequency correlated with poorer outcomes on developmental testing at all time points, but particularly at 12 months and beyond. Patients with higher seizure frequency during infancy continued to perform worse developmentally through 24 months. A logistic model looking at the individual impact of infantile spasms, seizure frequency, and age of seizure onset as predictors of developmental delay revealed that age of seizure onset was the most important factor in determining developmental outcome. Conclusions Results of this study further define the relationship between seizures and developmental outcomes in young children with TSC. Early seizure onset in infants with TSC negatively impacts very early neurodevelopment, which persists through 24 months of age.