Tuberous Sclerosis Complex Population Research Articles

Cenobamate's Efficacy for Seizure Treatment in Tuberous Sclerosis Complex

BackgroundEpilepsy is prevalent, and seizure control is challenging in patients with tuberous sclerosis complex (TSC). Cenobamate (CBM) has proven efficacy in several studies; however, its benefit in the TSC population is not known. MethodsWe performed a retrospective review of patients with TSC who received adjunctive CBM for seizure treatments. We assessed treatment efficacy by comparing seizure frequencies three months before CBM (baseline) and those at 3-, 6-, 12-, and 18- month follow-ups. ResultsWe identified 70 patients with TSC receiving CBM and excluded 16 with insufficient data. Fifty-four patients aged 2 to 39 years, with an average baseline seizure of 66.1 ± 88.9 per month, were analyzed. Treatment retention rates at 3, 6, 12, and 18 months were 94.4%, 79.6%, 66.7%, 44.4%, and responder rates (proportions of patients who remained on treatment and had ≥50% seizure reduction) were 38.1%, 51.7%, 53.1%, and 59.1%, respectively. Seizure-free rates at these respective follow-ups were 7.1%, 13.8%, 6.3%, and 9.1%. For patients experiencing reduced seizures, the mean percentage of change ranged from 61.5% to 74.6%. Side effects were common (64.8%), particularly sedation (42.6%), behavioral disturbance (24.1%), and gastrointestinal disturbance (22.2%). ConclusionsMost patients in this study showed seizure reduction; however, the overall responder and seizure-free rates were lower than the literature, likely due to the unique underlying epileptogenesis in TSC and the challenges of tolerating CBM. The lower treatment retention rates signal areas for improvement in concurrent medication adjustment practices.

Correlation between epilepsy and genotype: A large retrospective tuberous sclerosis complex cohort

Objective: To describe the first large population (n = 297) with tuberous sclerosis complex (TSC) in China and to examine the relationship between variants (type and location) and epilepsy. Methods: All exons and intron-exon boundaries of TSC1/TSC2 were sequenced with next-generation sequencing, and the distribution of several variants and associations between variant types and epilepsy were investigated. Results: Epilepsy occurred in 83.5% (248/297) of the individuals. The TSC1/TSC2 gene variant detection rate was 89.6% (266/297). The rate of epilepsy was significantly higher in the TSC2 group than in the TSC1 (p = 0.02) and no mutation identified (NMI) groups (p = 0.0005). TSC2 individuals are more likely to have spasms than TSC1 individuals (p =0.03). The age at epilepsy onset of individuals in the TSC2 group was younger than that of individuals in the TSC1 group (p = 0.008) and NMI group (p = 0.01). The age at epilepsy onset with truncated variants in the TSC1 group was significantly younger than that of individuals with nontruncated variants (p = 0.0001). The rate of epilepsy was significantly higher if variants occurred in the functional domain than in the nonfunctional domain in TSC2 individuals (p = 0.02). Conclusion: This was the first large cohort study of the Chinese TSC population in which a comparative analysis of genotype and epilepsy was conducted. Individuals with TSC2 variants appeared to have more severe epileptic phenotypes, such as younger age at epilepsy onset, than those with TSC1 variants and NMI, and individuals with variants that occurred in TSC2 functional domains were more prone to epilepsy and had a younger age at epilepsy onset.

Sirolimus Can Increase the Disappearance Rate of Cardiac Rhabdomyomas Associated with Tuberous Sclerosis: A Prospective Cohort and Self-Controlled Case Series Study

To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups. The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described. A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P=.027) and female patients (hazard ratio=2.08, P=.015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis. Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated.

Health utilities and quality of life in individuals with tuberous sclerosis complex (TSC) who experience epileptic seizures: A web-based survey

ObjectivesIndividuals with tuberous sclerosis complex (TSC) experience a wide range of health impacts, including epileptic seizures, negatively impacting their health-related quality of life (HRQoL). Health state utility values (HSUVs) are index values representing HRQoL and are used as key inputs for health economic analyses. Such data are currently very limited in the TSC population. The objective of this study was to generate HSUVs for TSC health states, defined by the number and type of seizures experienced in the previous week, and to compare with UK normative values. MethodsThis cross-sectional study involved 186 participants (individuals with TSC = 61, caregivers reporting for individuals with TSC = 125) from Europe and North America who completed a web-based survey. Participants completed the [EuroQol - 5 dimensions - 3 levels] (self-report version for individuals with TSC or proxy version 1 for caregivers). ResultsThe mean age of individuals with TSC was 27.3 years (self-reported: 41.3 years, caregiver-reported: 20.5 years); 56% were males. Most individuals with TSC (71%) reported experiencing between one and ten seizures in the week prior to participating in the study. The most frequently reported type of seizure was focal: simple partial (50%). Across all participants (combined self-report and caregiver-report), the mean HSUV was 0.474 (95% confidence interval [CI]: 0.424–0.524), significantly lower than the UK norm (0.856, 95%CI: 0.848–0.864) [1]. Mean HSUV and HRQoL scores were consistently lower when reported by caregivers than when self-reported by individuals with TSC (HSUV = 0.351 vs. 0.727). This is in part because caregivers reported for individuals with TSC who experienced more frequent and severe seizures than those who were able to self-report. HSUVs incrementally decreased with the experience of more frequent (1–5 per week: HSUV = 0.666 vs. >20: HSUV = 0.290) and more severe seizures (focal: simple partial: HSUV = 0.450 vs. generalized: convulsive: HSUV = 0.194). ConclusionsThe HRQoL and HSUV index scores indicate substantial impairment among individuals with TSC; HSUVs were shown to decrease considerably with increases in seizure frequency or seizure severity, indicating that more burdensome seizure health states are associated with poorer HRQoL.

Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex

Tuberous sclerosis complex (TSC), a heritable neurodevelopmental disorder, is caused by mutations in the TSC1 or TSC2 genes. To date, there has been little work to elucidate regional TSC1 and TSC2 gene expression within the human brain, how it changes with age, and how it may influence disease. Using a publicly available microarray dataset, we found that TSC1 and TSC2 gene expression was highest within the adult neo-cerebellum and that this pattern of increased cerebellar expression was maintained throughout postnatal development. During mid-gestational fetal development, however, TSC1 and TSC2 expression was highest in the cortical plate. Using a bioinformatics approach to explore protein and genetic interactions, we confirmed extensive connections between TSC1/TSC2 and the other genes that comprise the mammalian target of rapamycin (mTOR) pathway, and show that the mTOR pathway genes with the highest connectivity are also selectively expressed within the cerebellum. Finally, compared to age-matched controls, we found increased cerebellar volumes in pediatric TSC patients without current exposure to antiepileptic drugs. Considered together, these findings suggest that the cerebellum may play a central role in TSC pathogenesis and may contribute to the cognitive impairment, including the high incidence of autism spectrum disorder, observed in the TSC population.

Sporadic versus Tuberous Sclerosis Complex–Associated Angiomyolipomas: Predictors for Long-Term Outcomes following Transcatheter Embolization

PurposeTo evaluate risk factors for long-term outcomes following embolization of sporadic versus tuberous sclerosis complex (TSC)–associated angiomyolipomas (AMLs). Materials and MethodsA retrospective review of consecutive transcatheter embolizations of renal AMLs between 2002 and 2014 was performed. Tumor volumetrics including density analysis were obtained. Treatment outcomes were assessed at 1 year after embolization using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and volumetric RECIST criteria. A total of 56 patients, 70% (39/56) of whom had TSC, underwent embolization of 72 renal AMLs. Embolization was most commonly performed (70/72, 97%) using microspheres (300–500 μm or 500–700 μm Embosphere). ResultsBetween the sporadic and TSC-associated populations, there was no difference in follow-up time (648 d vs 583 d, P = .78), initial tumor diameter (6.68 cm vs 5.71 cm, P = .09), or percent tumoral fat content (39.5% vs 8.6%, P = .35). Progressive disease was noted in 9 TSC-associated AMLs by volume and 3 TSC-associated AMLs by diameter but in no sporadic AMLs. Growth suppression curves were remarkable for rebound growth in TSC patients, particularly in TSC patients younger than 18 years. Patient age (P = .007) and tumor volume (P = .03) were found to correlate with tumor regrowth within the TSC population. No difference was found in median change in total volume after embolization based on fat content (−57.9% vs −54.2%, P = .68). ConclusionsTSC, patient age, and tumoral volume before embolization are risk factors for AML growth following embolization. Intratumoral fat content was not found to predict response to embolization.

Do patients with tuberous sclerosis complex have an increased risk for malignancies?

Tuberous Sclerosis Complex (TSC) is generally characterized by the presence of benign tumors, but some patients with malignancies have been reported in the literature. We examined a large Italian TSC population (240 individuals followed from 2001 to 2015, aged 3 months-74 years), assessing the frequency of malignancies to determine whether there is an increased risk for cancer in this disorder, and looking for possible features associated with the development of neoplasia. Fifteen patients had malignancies (6.25%); median age at diagnosis was 37.5 years (range of 1.6-58). Five of seven renal tumors were renal cell carcinomas. Eight patients had a non-renal malignancy (3.3%), but we did not find a more prevalent type of cancer. No patient developed more than one malignancy. The prevalence of all malignant tumors was compatible with the prevalence in the general population (5.6%, 95%CI 2.99-9.31%, vs. 4.4% in Italy). Median age at cancer diagnosis was lower (37.5 years, 95%CI 28.6-44.7, vs. 66.0 years). Two patients (13.3%) died of their cancer, while outcome was favorable in the remaining individuals. Malignant tumors were more frequently diagnosed in patients with mutations in TSC1 when compared to TSC2 and patients with no mutation identified (P = 0.032). Our study demonstrated that TSC patients do not seem to have an increased risk for malignancies besides renal cell carcinoma. However, when cancer develops, age at diagnosis is lower than in the general population, and malignant tumors are more frequently diagnosed in patients with mutations in TSC1. Further studies are needed to confirm these data. ©2016 Wiley Periodicals, Inc.

2. Characterization of the tuberous sclerosis complex population in the province of Quebec: Healthcare services utilization and long term outcome

Background Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can present with many disabling neurological disorders, the most common being epilepsy. Although it is a chronic multi-system disease, healthcare utilization and long-term outcome of subjects with TSC are not yet well defined. The goal of this study was to evaluate the direct cost and long-term outcome of TSC in the province of Quebec, compared to other forms of epilepsy and healthy controls. Methods Our provincial health care database was interrogated to determine use of medical services by patients with TSC, epilepsy and healthy controls from 1996 to 2011. Data on demographics, outcomes and health care utilization were analyzed. Results 1004 TSC, 41,934 with epilepsy and 41,934 controls were identified. The prevalence of TSC was 1/7872 compared to 1/189 for epilepsy. TSC experienced more hospitalizations, medical visits and prescription drug use. Their most common admission diagnosis was seizures and age at death was significantly lower: 61.3 years old for TSC vs 69.6 and 76.6 years old for epilepsy and controls ( p 0.001 ). Conclusions TSC subjects have a significantly higher burden of disease than other subjects with epilepsy. These results stress the need for specialized services in this population through the lifespan.

Autism spectrum disorder in tuberous sclerosis complex: searching for risk markers.

BackgroundNeuropsychiatric disorders are present in up to 90 % of patients with Tuberous Sclerosis Complex (TSC), and represent an important issue for families. Autism Spectrum Disorder (ASD) is the most common neurobehavioral disease, affecting up to 61 % of patients. The aims of this study were: 1) to assess the prevalence of ASD in a TSC population; 2) to describe the severity of ASD; 3) to identify potential risk factors associated with the development of ASD in TSC patients.MethodsWe selected 42 individuals over age 4 years with a definite diagnosis of TSC and followed at a TSC clinic in Northern Italy. We collected and reported clinical and genetic data, as well as cognitive level, for each of them. We administered the Social Communication Questionnaire (SCQ) as a reliable screening tool for ASD, and performed comparisons between the average scores and each clinical and genetic feature.ResultsSeventeen out of 42 patients (40.5 %) had a score at the SCQ suggestive of ASD (≥15 points). When calculated for each cognitive level category, the average SCQ score tended to be progressively higher in patients with a worse cognitive level, and the number of pathological SCQ scores increased with worsening of intellectual disability. With respect to ASD severity, the scores were equally distributed, indicating that the degree of ASD in TSC patients may have a large variability. By comparing the average SCQ scores with the clinical features, we found statistically significant correlations with epilepsy, seizure onset before age one year, spasms, mutations in TSC2, cognitive level, sleep disorders, and other psychiatric problems, but not with seizure frequency, tubers localization and gender.ConclusionsOur study showed a prevalence of ASD of 40.5 %, confirming the higher risk for this disorder in patients with TSC. However, the severity seems to have a notable variability in TSC patients. Risk factors for ASD are epilepsy, infantile spams, and mutations in TSC2.

Pancreatic neuroendocrine tumors in patients with tuberous sclerosis complex

We explored pancreatic neuroendocrine tumors (PanNETs) associated with tuberous sclerosis complex (TSC) to determine their incidence in the TSC population; define their clinical, radiological, and pathological characteristics; and investigate their association with underlying genotypes. Retrospectively reviewed abdominal imaging of 219 patients with TSC, evaluating the incidence, size, and architecture of pancreatic lesions. Pathology records at Massachusetts General Hospital (MGH) were reviewed for all PanNET diagnoses in patients with TSC. Literature was reviewed for TSC-related PanNET cases. Nine patients with TSC were found to have a pancreatic lesion(s) on abdominal imaging and six patients have been diagnosed with a PanNET by pathology at MGH. Twelve cases of TSC-associated PanNETs have been reported in the literature. Of these 18 PanNET cases, one third were cystic, and the average age at resection was 26 years. Germline TSC2 mutations were found in all patients for whom genetic data were available (n = 3). We did not identify pancreatic angiomyolipomas in this series. Our results suggest that PanNETs are the most common pancreatic lesion in patients with TSC. Focal pancreatic mass lesions, solid or cystic, in patients with TSC should be considered possible PanNETs, and resection of the lesion may be clinically indicated.

The clinical utility of the Social Responsiveness Scale and Social Communication Questionnaire in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is often associated with epilepsy, mental retardation, and autism spectrum disorders (ASDs). Thus, screening for ASDs is important when evaluating these individuals. We examined the utility of the Social Responsiveness Scale (SRS) and Social Communication Questionnaire (SCQ), two measures for screening for ASDs, in a TSC population. Twenty-one children were evaluated, with 52.4% classified as having ASDs on the SRS and 42.9% classified as such on the SCQ. Number of antiepileptic drugs significantly correlated with SRS Total score, as did level of intellectual functioning. Evidence for convergent validity was obtained between the SRS and SCQ Total scores ( r = 0.605). Moreover, all SRS subscales correlated with SCQ Total score ( r > 0.400). All SCQ subscales except for Communication correlated with SRS total. Overall, the results demonstrate that these questionnaires appear to be effective screens for ASDs in a TSC population and are measuring similar constructs.

Self-injurious behavior and tuberous sclerosis complex: Frequency and possible associations in a population of 257 patients

Self-injurious behavior (SIB) has been observed in people with tuberous sclerosis complex (TSC), although the frequency of SIB in TSC is largely unknown. SIB is associated with intellectual and developmental disabilities, but there is no single cause of SIB. We retrospectively examined the frequency of SIB in a population of 257 patients with TSC and determined possible associations with SIB. We found a 10% frequency of SIB in our TSC population. When compared with patients without psychiatric symptoms, we identified a significantly higher rate of electroencephalographic interictal spikes in the left frontal lobe and a significantly lower number of tubers in the left occipital, parietal, and posterior temporal lobes. We also found that frequency of TSC2 mutation, history of infantile spasms, history of seizures, mental retardation, and autism are significantly associated with SIB.