Stiripentol for Drug-Resistant Epilepsy Treatment in Tuberous Sclerosis Complex.

BACKGROUND: Drug-resistant epilepsy (DRE) is common in tuberous sclerosis complex (TSC). The role of stiripentol (STP) in seizure treatment in this population is not well understood. This study evaluates the efficacy and tolerability of STP in patients with TSC with DRE. METHODS: We performed a retrospective review of patients with TSC with DRE. Seizure frequencies at 1 month before (baseline) and 1, 3, 6, and 12 months after STP initiation were collected. RESULTS: Of the 1492 patients, 13 received STP and the number of patients with ≥50% seizure reduction at 1, 3, 6, and 12 months was 6/13 (46.2%), 4/13 (30.8%), 8/13 (61.5%), and 6/13 (46.2%), respectively. Six patients (46.2%) had favorable outcomes with persistent seizure reduction through 12 months. Their mean (±S.D.) percentage of seizure reduction at 1, 3, 6, and 12 months was 68.1 (±22.0), 71.3 (±23.2), 75.7 (±23.5), and 75.7 (±23.5), respectively. One patient had worsening seizures throughout the STP course. Three patients did not have seizure reduction until after 6 months, and 2 had initial seizure reduction before worsening. Younger age (P value <0.001), early STP treatment (P value <0.001), higher doses (P value = 0.004), and higher baseline seizure frequency (P value = 0.01) were associated with favorable outcomes. Side effects were seen in 85% of our cohort. CONCLUSIONS: About 46% of the patients had favorable outcomes. Younger age, early STP treatment, higher doses, and higher baseline seizure frequency were significantly associated with favorable outcomes.

Cellular and molecular characterization of two novel asparagine synthetase gene mutations linked to asparagine synthetase deficiency.

Asparagine synthetase (ASNS) catalyzes synthesis of asparagine (Asn) and Glu from Asp and Gln in an ATP-dependent reaction. Asparagine synthetase deficiency (ASNSD) results from biallelic mutations in the ASNS gene. Affected children exhibit congenital microcephaly, continued brain atrophy, seizures, and often premature mortality. However, the underlying mechanisms are unclear. This report describes a compound heterozygotic ASNSD child with two novel mutations in the ASNS gene, c.1118G>T (paternal) and c.1556G>A (maternal), that lead to G373V or R519H ASNS variants. Structural mapping suggested that neither variant participates directly in catalysis. Growth of cultured fibroblasts from either parent was unaffected in Asn-free medium, whereas growth of the child's cells was suppressed by about 50%. Analysis of Asn levels unexpectedly revealed that extracellular rather than intracellular Asn correlated with the reduced proliferation during incubation of the child's cells in Asn-free medium. Our attempts to ectopically express the G373V variant in either HEK293T or JRS cells resulted in minimal protein production, suggesting instability. Protein expression and purification from HEK293T cells revealed reduced activity for the R519H variant relative to WT ASNS. Expression of WT ASNS in ASNS-null JRS cells resulted in nearly complete rescue of growth in Asn-free medium, whereas we observed no proliferation for the cells expressing either the G373V or R519H variant. These results support the conclusion that the coexpression of the G373V and R519H ASNS variants leads to significantly reduced Asn synthesis, which negatively impacts cellular growth. These observations are consistent with the ASNSD phenotype.

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. Thus, the prevalence of many findings is unknown. To answer this, we categorized the clinical reads of 1398 thoracoabdominal scans from 649 patients of all ages in the Cincinnati Children's Hospital TSC Repository Database. RESULTS: Typical TSC findings were present in many patients: kidney cysts (72%), kidney fat-containing angiomyolipomas (51%), kidney lipid-poor angiomyolipomas (27%), liver angiomyolipomas (19%), and lung nodules thought to represent multifocal micronodular pneumocyte hyperplasia (MMPH) (18%). While many features were more common in TSC2 patients, TSC1 patients had a higher prevalence of MMPH than TSC2 patients (24% versus 13%, p = 0.05). Many rare findings (e.g., lymphatic malformations and liver masses) are more common in TSC than in the general population. Additionally, most thoracoabdominal imaging findings increased with age except kidney cysts which decreased, with the 0-10 years age group having the highest percentage (69% 0-10 years, 49% 10-21 years, 48% 21 + years, p < 0.001). Finally, in our population, no patients had renal cell carcinoma found on abdominal imaging. CONCLUSIONS: These results show that regular thoracoabdominal scans in TSC may show several findings that should not be ignored or, conversely, over-reacted to when found in patients with TSC. Female sex, TSC2 mutation, and age are risk factors for many thoracoabdominal findings. The data suggest novel interactions of genetic mutation with pulmonary nodules and age with renal cysts. Finally, in agreement with other works, these findings indicate that several rare thoracoabdominal imaging findings occur at higher rates in the TSC population than in the general population. This work supports obtaining detailed thoracoabdominal imaging in patients with TSC.

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. Cluster and factor analyses for each TAND symptom were performed. Factor scores were then calculated for participants, and a K-means cluster analysis of these scores was used to empirically identify distinct overall TAND symptom profiles occurring in TSC. RESULTS: A total of 1545 checklists was completed for 668 participants (37% adults and 63% children). Approximately 90% of participants reported at least one TAND symptom with an average of 12 symptoms (out of 29). Symptom rates ranged between 5 and 60%. The most common symptoms were neuropsychologic symptoms. A seven-cluster and seven-factor solution were found to be optimal. K-means cluster analysis resulted in a seven-profile solution, ranging from low to high symptom burden. CONCLUSION: This study is the first to identify natural phenotypic profiles of TAND symptoms. Study of specific TAND subpopulations with shared profiles may facilitate better understanding of the underlying biology of TAND and better assessment of more targeted treatments.

Adjunctive everolimus therapy for tuberous sclerosis complex-associated refractory seizures: Results from the postextension phase of EXIST-3.

OBJECTIVE: Epilepsy is highly prevalent in patients with tuberous sclerosis complex (TSC). Everolimus showed higher efficacy than placebo for seizures in the primary analysis of the EXIST-3 study. Here, we present the long-term outcomes of everolimus at the end of the postextension phase (PEP; data cutoff date: October 25, 2017). METHODS: After completion of the extension phase, patients were invited to continue everolimus in the PEP with everolimus (targeted trough concentration = 5-15 ng/ml, investigator-judged). Efficacy assessments included changes in seizure status during the PEP collected at 12-week intervals as parent/caregiver-reported data through a structured questionnaire. RESULTS: Among 361 patients, 343 entered the extension phase and 249 entered the PEP. After 12 weeks in the PEP, 18.9% (46/244) of patients were seizure-free since the last visit of the extension phase and 64.8% (158/244) had a stable/improved seizure status. At 24 weeks, the corresponding percentages were 18.2% (42/231) and 64.5% (149/231). Among 244 patients, the response rate was 32.8% (80/244) during the 12-week maintenance period of the core phase and 63.9% (156/244) at the end of the extension phase. Of the 149 responders at the end of the extension phase, 70.5% were seizure-free or had stable/improved seizure status. Long-term efficacy data showed persistent responses were observed in 183 of 361 patients (50.7%); 63.9% of these patients had a response that lasted at least 48 weeks. The most frequent Grade 3-4 adverse events (≥2% incidence) reported throughout the study were pneumonia, status epilepticus, seizure, stomatitis, neutropenia, and gastroenteritis. Four patients died during the study. SIGNIFICANCE: The final analysis of EXIST-3 demonstrated the sustained efficacy of everolimus as adjunctive therapy in patients with TSC-associated treatment-refractory seizures, with a tolerable safety profile.

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. Side effects previously identified in well-designed clinical trials tend to be mild and readily manageable. Regulatory approvals for the treatment of TSC have expanded the use of everolimus and sirolimus clinically, enlarging clinician experience and enabling identification of potential treatment-related effects that are rarer than could be identified or recognized in previous clinical trials. METHODS: The medical records of clinical patients from our TSC center who were treated with an mTORi and later developed diabetes mellitus (DM) were analyzed and compared with those who were not treated with an mTORi. Eight individuals received detailed analysis, including laboratory results, concomitant medications, and body mass indices. RESULTS: Among the 1576 individuals with TSC, 4% taking an mTORi developed diabetes compared with 0.6% of those not on mTORi, showing a significant interaction between DM and mTORi (chi-square = 18.1, P < 0.001). Details of eight patients who developed DM were presented. CONCLUSIONS: The long-term use of mTORi agents in TSC may contribute to a risk of diabetes. Early detection can be critical in management. Additional studies are need to further investigate a causal relationship, but clinicians should be aware of this possible association when initiating and monitoring ongoing treatment.

RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex.

Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.

Lymphangioleiomyomatosis Association with Underlying Genotype in Patients with Tuberous Sclerosis Complex.

Rationale: Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease caused by mutations in the tuberous sclerosis complex (TSC) genes TSC1 and TSC2.Objectives: To examine the association between TSC mutation subtypes and the prevalence of LAM in women with TSC.Methods: Adult women seen at the Cincinnati Children's Hospital Medical Center's TSC clinic were stratified into the following three groups: those with TSC1 mutation, those with TSC2 mutation, and those with no mutation identified (NMI). Individual TSC manifestations were ascertained by blinded review of chest computed tomographic scans (LAM, multifocal micronodular pneumocyte hyperplasia, and sclerotic bone lesions) and chart review (all other manifestations). The association between mutation status and TSC manifestations was assessed by the Wilcoxon rank-sum test.Results: Our cohort consisted of 55 TSC women, including 30/55 (55%) with TSC2, 12/55 (22%) with TSC1, and 13/55 (23%) with NMI. Twenty-three women (42%) had characteristic cysts consistent with LAM, of whom 16 had TSC2 mutations and seven had NMI. The prevalence of LAM was higher in women with TSC2 mutations compared with women with TSC1 mutations (16/29 [55%] vs. 0/12; P = 0.003). Similarly, renal angiomyolipomas were more common in women with TSC2 mutations compared with women with TSC1 mutations (29/30 [97%] vs. 6/12 [50%]; P = 0.01). There was no association between TSC mutation subtype and the presence of multifocal micronodular pneumocyte hyperplasia, sclerotic bone lesions, and skin or brain involvement. Serum VEGF-D (vascular endothelial growth factor-D) concentrations (median [95% confidence interval]) tended to be higher in patients harboring TSC2 mutations compared with patients with TSC1 mutations (725 pg/ml [612-1,317] vs. 331 pg/ml [284-406]; P = 0.03) and in patients with LAM compared with patients without LAM (725 pg/ml [563-1,609] vs. 429 pg/ml [357-773]; P = 0.02).Conclusions: LAM and angiomyolipomas are more common in women with TSC harboring TSC2 mutations compared with women with TSC1 mutations. Serum VEGF-D is a useful biomarker to suggest the presence of LAM in women with 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 (n = 24; 14 males; mean age, 14.5 years ± 7.8 [standard deviation] at first examination). One reviewer drew regions of interest around psoas muscles at L3 to measure cross-sectional area. Multiple linear mixed-effect modeling was performed to evaluate the association between muscle mass and the covariates over time. Results: The 24 patients underwent a total of 129 abdominal CT or MRI examinations. Median duration of mTOR inhibition at last examination was 106 months (range, 1310-3717 days). There was no significant association between the duration of mTOR inhibitor therapy and psoas muscle area on multiple linear mixed-effect modeling (P = .055); however, patient height and height squared were significant predictors of psoas area (P = .014 and P < .0001, respectively). Conclusion: Duration of mTOR inhibition in TSC was not significantly associated with a decrease in psoas muscle area, suggesting that chronic mTOR inhibition is not associated with sarcopenia.Keywords: CT, MR-Imaging, Pediatrics© RSNA, 2020.

Effect of everolimus on renal function in patients with tuberous sclerosis complex: evidence from EXIST-1 and EXIST-2.

BACKGROUND: A reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure. METHODS: The long-term effects of EVE on renal function (∼4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5 mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10 mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3 months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: A total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88 mL/min/1.73 m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests. CONCLUSIONS: The use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients.ClinicalTrials.gov identifiers NCT00789828 and NCT00790400.

Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial.

BACKGROUND: EXamining everolimus In a Study of Tuberous sclerosis 3 (EXIST-3) demonstrated significantly reduced seizure frequency (SF) with everolimus vs placebo. In this study, we evaluate the long-term efficacy and safety of everolimus for tuberous sclerosis complex (TSC)-associated treatment-refractory seizures. METHODS: After completion of the core phase, patients could enter an open-label extension phase and receive everolimus (target exposure, 3-15 ng/mL) for ≥48 weeks. Efficacy end points included change from baseline in average weekly SF expressed as response rate (RR, ≥50% reduction) and median percentage reduction (PR). RESULTS: Of 366 patients, 361 received everolimus in core/extension phases. The RR was 31% (95% CI, 26.2-36.1; N = 352) at week 18, 46.6% (95% CI, 40.9-52.5; N = 298) at 1 year, and 57.7% (95% CI, 49.7-65.4; N = 163) at 2 years. Median PR in SF was 31.7% (95% CI, 28.5-36.1) at week 18, 46.7% (95% CI, 40.2-54) at 1 year, and 56.9% (95% CI, 50-68.4) at 2 years. Ninety-five patients (26.3%) discontinued everolimus before 2 years; 103 (28.5%) had <2 years of follow-up at study cutoff, and 40% were exposed to everolimus for ≥2 years. An analysis classifying discontinued patients as nonresponders showed an RR of 30.2% (95% CI, 25.5-35.2; N = 361) at week 18, 38.8% (95% CI, 33.7-44.1; N = 358) at 1 year, and 41% (95% CI, 34.6-47.7; N = 229) at 2 years, suggesting sustained benefit over time. The incidence of grade 3/4 adverse events (AEs) (any cause) was 40.2%, and 13% discontinued because of AEs (pneumonia [1.7%] and stomatitis [1.4%]). Two deaths were suspected to be treatment-related (pneumonia and septic shock). CONCLUSIONS: Sustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile was consistent with the core phase with no new safety concerns. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.

Measuring Health-Related Quality of Life in Tuberous Sclerosis Complex - Psychometric Evaluation of Three Instruments in Individuals With Refractory Epilepsy.

Tuberous sclerosis complex (TSC) is a rare genetic disease associated with significant disease burden and considerable impact on health-related quality of life (HRQL). Currently no disease-specific clinical outcome assessments evaluate HRQL in individuals with TSC. A multi-center phase III study EXIST-3 (NCT01713946) assessed the efficacy and safety of two trough exposure ranges (Low exposure, LE: 3-7 ng/mL and high exposure, HE: 9-15 ng/mL) of adjunctive everolimus in patients aged 2-65 years with TSC and refractory partial-onset seizures (N = 366). Three age-specific HRQL measures were included as secondary endpoints including: quality of life in childhood epilepsy (QOLCE; caregiver-report for aged 2- < 11), the Quality of Life in Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48; self-report, aged ≥ 11- < 18), and the Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P; self-report, aged ≥ 18). Intellectual ability was evaluated using the Wechsler Non-Verbal (WNV) Scale of Ability. Post hoc analyses were performed on the core phase primary data from EXIST-3 to evaluate the psychometric properties of the HRQL measures and calculate meaningful change estimates. Results showed that a significant subset of the trial sample (4-21 year olds) scored in the intellectual disability range, as assessed by the WNV. Psychometric analyses of the three epilepsy measures (including reliability, validity, and ability to detect change) supported the appropriateness for use in TSC. Distribution-based meaningful change estimates were generated for each HRQL measure, with estimates for the QOLIE-31-P total score largely consistent with the published literature. To our knowledge, this is the first evaluation using clinical trial data to establish the psychometric properties of the QOLCE, QOLIE-AD-48, and QOLIE-31-P for use in individuals with TSC. These findings increase confidence in the measures as valid and reliable for use in clinical trials and future research in patients with TSC.

Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial.

BACKGROUND: Epilepsy occurs in 70-90% of patients with tuberous sclerosis complex. We aimed to assess the efficacy and safety of adjunctive everolimus for treatment-refractory seizures associated with tuberous sclerosis complex in paediatric patients enrolled in the EXIST-3 trial, a double-blind, placebo-controlled, randomised, phase 3 study. METHODS: This post-hoc analysis focused on paediatric patients (age <18 years) in the EXIST-3 trial, which consisted of baseline (8 weeks), core (18 weeks), and extension phases (≥48 weeks) and was done at 99 centres in 25 countries worldwide. Briefly, patients with tuberous sclerosis complex-associated treatment-refractory seizures, who were receiving a stable dose of one to three antiepileptic drugs, were randomly assigned (1:1:1) to receive placebo, low-exposure everolimus (3-7 ng/mL), or high-exposure everolimus (9-15 ng/mL). Following the core phase, patients could enter the extension phase to receive everolimus at a targeted exposure range of 3-15 ng/mL up to 48 weeks after the last patient had completed the core phase. Efficacy endpoints were response rate (≥50% of reduction from baseline in average weekly seizure frequency) and median percentage reduction in seizure frequency during the 12-week maintenance period of the core phase, and at 12-week intervals throughout the extension phase. This study is registered with ClinicalTrials.gov, number NCT01713946. FINDINGS: Between July 3, 2013, and May 29, 2015, 299 paediatric patients enrolled in the trial. In the younger subgroup (<6 years; n=104), 34 received placebo, 33 low-exposure everolimus, and 37 high-exposure everolimus; in the older subgroup (≥6 years to <18 years; n=195), 62 received placebo, 63 low-exposure everolimus, and 70 high-exposure everolimus. At the end of the core phase, response rate was higher in the treatment groups than placebo in both the younger subgroup (17·6% [6·8-34·5] for placebo vs 30·3% [95% CI 15·6-48·7; p=0·2245] for low-exposure everolimus vs 59·5% [42·1-75·2; p=0·0003] for high-exposure everolimus) and the older subgroup (12·9% [5·7-23·9] vs 27·0% [16·6-39·7; p=0·0491] vs 30·0% [19·6-42·1; p=0·0179]), as were median reduction in seizure frequency (12·3% [95% CI -10·1 to 24·8] vs 29·3% [95% CI 13·4 to 46·3; p=0·0474] vs 54·7% [43·5 to 73·1; p<0·0001] in younger patients; 13·5% [-3·0 to 26·8] vs 31·0% [16·1 to 42·9; p=0·0128] vs 34·8% [26·7 to 41·3; p=0·0006] in older patients). The efficacy persisted, with sustained seizure reduction after 1 year of treatment across both paediatric subgroups (response rate 48·9% [95% CI 38·1-59·8] for the younger subgroup vs 47·2% [39·3-55·2] for the older subgroup; median percentage reduction in seizure frequency 48·4% [95% CI 34·3-73·6] vs 48·0% [38·2-57·5]). At the cutoff date for the extension phase, grade 3 or 4 adverse events were reported in 45 (45%) younger patients (commonly pneumonia [n=16]) and 74 (38%) older patients (commonly pneumonia [n=8] and stomatitis [n=6]). Two deaths (pneumonia, which was suspected to be treatment-related, and sudden unexplained death due to epilepsy) were reported. INTERPRETATION: Adjunctive everolimus resulted in sustained reductions in seizure frequency after 1 year and was well tolerated in paediatric patients with treatment-refractory seizures associated with tuberous sclerosis complex. FUNDING: Novartis Pharmaceuticals Corporation.

Thoracoabdominal imaging of tuberous sclerosis.

Imaging of tuberous sclerosis complex has rapidly evolved over the last decade in association with increased understanding of the disease process and new treatment modalities. Tuberous sclerosis complex is best known for the neurological symptoms and the associated neuroimaging findings, and children with tuberous sclerosis complex require active surveillance of associated abnormalities in the chest, abdomen and pelvis. Common findings that require regular imaging surveillance are angiomyolipomas in the kidneys and lymphangioleiomyomatosis in the chest. However multiple rarer associations have been attributed to tuberous sclerosis complex and should be considered by radiologists reviewing any imaging in these children. In this review the authors discuss the spectrum of imaging findings in people with tuberous sclerosis complex, focusing on MR imaging findings in the chest, abdomen and pelvis.

Everolimus dosing recommendations for tuberous sclerosis complex-associated refractory seizures.

OBJECTIVE: The present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin ) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin . METHODS: A model-based approach was used to predict patients' daily Cmin . Time-normalized Cmin (TN-Cmin ) was calculated as the average predicted Cmin in a time interval. TN-Cmin was used to link exposure to efficacy and safety end points via model-based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure-response relationship for seizure frequency (SF). An extended Cox regression model was used to link exposure to the time to first adverse event. RESULTS: There was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN-Cmin and SF, regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN-Cmin were not associated with statistically significant increases in the risk of stomatitis or infections. SIGNIFICANCE: The recommended TDM is to target everolimus Cmin within a range of 5-7 ng/mL initially and 5-15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP3A4/P-glycoprotein inducers/inhibitors.

The effect of everolimus on renal angiomyolipoma in pediatric patients with tuberous sclerosis being treated for subependymal giant cell astrocytoma.

BACKGROUND: Patients with tuberous sclerosis complex (TSC) often have multiple TSC-associated hamartomas, particularly in the brain and kidney. METHODS: This was a post hoc analysis of pediatric patients being treated for subependymal giant cell astrocytomas (SEGAs) during the phase 3, randomized, double-blind, placebo-controlled EXIST-1 trial. Patients were initially randomly assigned to receive everolimus 4.5 mg/m2/day (target blood trough 5-15 mg/dl) or placebo and could continue in an open-label extension phase. Angiomyolipoma response rates were analyzed in patients aged <18 years with ≥1 target angiomyolipoma lesion at baseline. Response was defined as the proportion of patients with a ≥50% reduction in the sum volume of target renal angiomyolipomata from baseline, in the absence of new target angiomyolipomata, a >20% increase in kidney volume from nadir, and angiomyolipoma-related bleeding ≥ grade 2. Tolerability was also assessed. RESULTS: Overall, this analysis included 33 patients. Renal angiomyolipoma response was achieved by 75.8% of patients (95% confidence interval, 57.7-88.9%), with sustained mean reductions in renal angiomyolipoma volume over nearly 4 years of treatment. In addition, most (≥80%) achieved clinically relevant reductions in angiomyolipoma volume (≥50%), beginning at week 24 and continuing for the remainder of the study. Everolimus was generally well tolerated in this subgroup, with most adverse events being grade 1 or 2 in severity. CONCLUSIONS: Although everolimus is currently not indicated for this use, this analysis from EXIST-1 demonstrates its long-term efficacy and safety for the treatment of renal angiomyolipoma in pediatric patients undergoing treatment for TSC-associated SEGA.

Pooled analysis of menstrual irregularities from three major clinical studies evaluating everolimus for the treatment of tuberous sclerosis complex.

OBJECTIVES: To determine the impact of everolimus on female fertility, including menstrual irregularities, secondary amenorrhea, and luteinizing and follicle stimulating hormone levels in female patients. DESIGN: A pooled analysis from 3 prospective studies consisting of a core phase (≥6 months) and a long-term follow-up open-label extension. SETTING: One phase 2 single-center and two phase 3 multicenter studies. PARTICIPANTS: Data were obtained from female participants, restricted to those between 10 and 55 years of age, during 1 of 3 of the described clinical trials of everolimus. Patients had received ≥ 1 dose of everolimus. MAIN OUTCOME MEASURES: Incidence of fertility events. RESULTS: A total of 43/112 patients (38.4%) experienced at least 1 menstrual irregularity. The most common events were amenorrhea (24.1%) and irregular menstruation (17.0%). Seven patients (6.3%) experienced grade 3/4 amenorrhea. When only the longest duration period of amenorrhea for each patient was considered, the median duration was 291 days. Fifteen patients attained menarche during the treatment period in any of the pooled studies. The mean age of menarche for this group was 12.4 years, similar to that of patients who were postmenarche at study entry (12.2 years). A total of 19/92 patients (20.7%) who were postmenarche at baseline or during the study experienced an irregular menstruation event. An increased luteinizing hormone level was reported as an adverse event in 3/112 patients (3%), and follicle-stimulating hormone levels were within normal limits for these patients. CONCLUSIONS: No new safety concerns emerged regarding endocrine function and menstruation in female patients with tuberous sclerosis complex-associated subependymal giant cell astrocytoma or angiomyolipoma, who were receiving everolimus. TRIAL REGISTRATION: ClinicalTrials.gov NCT00411619, NCT00789828, NCT00790400.