Development and internal validation of a clinical risk score to predict incident renal and pulmonary tumours in people with tuberous sclerosis complex.

OBJECTIVE: This study aims to develop and internally validate a clinical risk score to predict incident renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) in people with tuberous sclerosis complex (TSC). STUDY DESIGN: Data from 2420 participants in the TSC Alliance Natural History Database were leveraged for these analyses. Logistic regression was used to predict AML and LAM development using 10 early-onset clinical manifestations of TSC as potential predictors, in addition to sex and genetic mutation. For our models, we divided AML into three separate outcomes: presence or absence of AML, unilateral or bilateral and whether any are ≥3 cm in diameter. The resulting regression models were turned into clinical risk scores which were then internally validated using bootstrap resampling, measuring discrimination and calibration. RESULTS: The lowest clinical risk scores predicted a risk of AML and LAM of 1% and 0%, while the highest scores predicted a risk of 99% and 73%, respectively. Calibration was excellent for all three AML outcomes and good for LAM. Discrimination ranged from good to strong. C-statistics of 0.84, 0.83, 0.83 and 0.92 were seen for AML, bilateral AML, AML with a lesion≥3 cm and LAM, respectively. CONCLUSION: Our work is an important step towards identifying individuals who could benefit from preventative strategies as well as more versus less frequent screening imaging. We expect that our work will allow for more personalised medicine in people with TSC. External validation of the risk scores will be important to confirm the robustness of our findings.

Outcome of emergency neurosurgery in patients with refractory and super-refractory status epilepticus: a systematic review and individual participant data meta-analysis.

Background: Refractory (RSE) and super-refractory status epilepticus (SRSE) are serious neurological conditions requiring aggressive management. Beyond anesthetic agents, there is a lack of evidence guiding management in these patients. This systematic review and individual participant data meta-analysis (IPDMA) seeks to evaluate and compare the currently available surgical techniques for the acute treatment of RSE and SRSE. Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Individual Participant Data (PRISMA-IPD). Only patients who underwent surgery while in RSE and SRSE were included. Descriptive statistics were used to compare various subgroups. Multivariable logistic regression models were constructed to identify predictors of status epilepticus (SE) cessation, long-term overall seizure freedom, and favorable functional outcome (i.e., modified Rankin score of 0-2) at last follow-up. Results: A total of 87 studies including 161 participants were included. Resective surgery tended to achieve better SE cessation rate (93.9%) compared to non-resective techniques (83.9%), but this did not reach significance (p = 0.071). Resective techniques were also more likely to achieve seizure freedom (69.1% vs. 34.4%, p = <0.0001). Older age at SE (OR = 1.384[1.046-1.832], p = 0.023) was associated with increased likelihood of SE cessation, while longer duration of SE (OR = 0.603[0.362-1.003], p = 0.051) and new-onset seizures (OR = 0.244[0.069-0.860], p = 0.028) were associated with lower likelihood of SE cessation, but this did not reach significance for SE duration. Only shorter duration of SE prior to surgery (OR = 1.675[1.168-2.404], p = 0.0060) and immediate termination of SE (OR = 3.736 [1.323-10.548], p = 0.014) were independently associated with long-term seizure status. Rates of favorable functional outcomes (mRS of 0-2) were comparable between resective (44.4%) and non-resective (44.1%) techniques, and no independent predictors of outcome were identified. Conclusion: Our findings suggest that emergency neurosurgery may be a safe and effective alternative in patients with RSE/SRSE and may be considered earlier during the disease course. However, the current literature is limited exclusively to small case series and case reports with high risk of publication bias. Larger clinical trials assessing long-term seizure and functional outcomes are warranted to establish robust management guidelines.

Trajectories of parent well-being in children with drug-resistant epilepsy.

OBJECTIVE: This longitudinal cohort study aimed to identify trajectories of parent well-being over the first 2 years after their child's evaluation for candidacy for epilepsy surgery, and to identify the baseline clinical and demographic characteristics associated with these trajectories. Parent well-being was based on parent depressive and anxiety symptoms and family resources (i.e., family mastery and social support). METHODS: Parents of 259 children with drug-resistant epilepsy (105 of whom eventually had surgery) were recruited from eight epilepsy centers across Canada at the time of their evaluation for epilepsy surgery candidacy. Participants were assessed at baseline and 6-month, 1-year, and 2-year follow-up. The trajectories of parents' depressive symptoms, anxiety symptoms, and family resources were jointly estimated using multigroup latent class growth models. RESULTS: The analyses identified three trajectories: an optimal-stable group with no/minimal depressive or anxiety symptoms, and high family resources that remained stable over time; a mild-decreasing-plateau group with mild depressive and anxiety symptoms that decreased over time then plateaued, and intermediate family resources that remained stable; and a moderate-decreasing group with moderate depressive and anxiety symptoms that decreased slightly, and low family resources that remained stable over time. Parents of children with higher health-related quality of life, fathers, and parents who had higher household income were more likely to have better trajectories of well-being. Treatment type was not associated with the trajectory groups, but parents whose children were seizure-free at the time of the last follow-up were more likely to have better trajectories (optimal-stable or mild-decreasing-plateau trajectories). SIGNIFICANCE: This study documented distinct trajectories of parent well-being, from the time of the child's evaluation for epilepsy surgery. Parents who present with anxiety and depressive symptoms and low family resources do not do well over time. They should be identified and offered supportive services early in their child's epilepsy treatment history.

Pre-Operative Predictors of Health-Related Quality of Life Two Years After Pediatric Epilepsy Surgery: A Prospective Cohort Study.

PURPOSE: Seizure freedom is an important predictor of health-related quality of life (HRQOL) after pediatric epilepsy surgery. This study aimed to identify the pre-operative predictors of HRQOL 2 years after epilepsy surgery in children with drug-resistant epilepsy. METHODS: This multicenter prospective cohort study assessed pre-operative predictors including child (demographics and clinical variables), caregiver (including caregiver depressive and anxiety symptoms) and family characteristics. HRQOL was assessed using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE)-55 pre-operatively and 2-years after surgery. Univariable linear regression analyses were done to identify significant preoperative predictors of HRQOL 2-years after surgery, followed by multivariable regression. RESULTS: Ninety-five children underwent surgery, mean age was 11.4 (SD=4.2) years, and 59 (62%) were male. Mean QOLCE scores were 57.4 (95%CI: 53.8, 61.0) pre-operatively and 65.6 (95%CI: 62.0, 69.1) after surgery. Univariable regression showed fewer anti-seizure medications (ß=-6.1 [95%CI: -11.2, -1.0], p = 0.019), older age at seizure onset (ß=1.6 [95%CI: 0.8, 2.4], p<0.001), higher pre-operative HRQOL (ß=0.7 [95%CI: 0.5, 0.8], p<0.001), higher family resources (ß=0.6 [95%CI: 0.3, 0.9], p<0.001), better family relationships (ß=1.7 [95%CI: 0.3, 3.1], p = 0.017) and lower family demands (ß=-0.9 [95%CI: -1.5, -0.4], p<0.001) were associated with higher HRQOL after surgery. Caregiver characteristics did not predict HRQOL after surgery (p>0.05). Multivariable regression showed older age at seizure onset (ß=4.6 [95%CI: 1.6, 7.6], p = 0.003) and higher pre-operative HRQOL (ß=10.2 [95%CI: 6.8, 13.6], p<0.001) were associated with higher HRQOL after surgery. CONCLUSION: This study underscores the importance of optimizing pre-operative HRQOL to maximize HRQOL outcome after pediatric epilepsy surgery.

A longitudinal cohort study of mediators of health-related quality of life after pediatric epilepsy surgery or medical treatment.

OBJECTIVES: The purpose of this longitudinal cohort study was to examine the variables that influence health-related quality of life (HRQOL) after epilepsy surgery in children. We examined whether treatment type (surgical vs medical therapy) and seizure control are related to other variables that have been shown to influence HRQOL, namely depressive symptoms in children with epilepsy or their parents, and the availability of family resources. METHODS: In total, 265 children with drug-resistant epilepsy were recruited from eight epilepsy centers across Canada at the time of their evaluation for candidacy for epilepsy surgery and were assessed at baseline, 6-month, 1-year, and 2-year follow-up. Parents completed the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) and measures of family resources and depression; children completed depression inventories. Causal mediation analyses using natural effect models were used to evaluate the extent to which the relationship between treatment and HRQOL was explained by seizure control, child and parent depressive symptoms, and family resources. RESULTS: Overall, 111 children underwent surgery and 154 were treated with medical therapy only. The HRQOL scores of surgical patients were 3.4 points higher (95% confidence interval [CI]: -0.2, 7.0) relative to medical patients at the 2-year follow-up after adjusting for baseline covariates, with 66% of the effect of surgery attributed to seizure control. Child or parent depressive symptoms and family resources had negligible mediation effects between treatment and HRQOL. The effect of seizure control on HRQOL was not mediated by child or parent depressive symptoms, or by family resources. SIGNIFICANCE: The findings demonstrate that seizure control is on the causal pathway between epilepsy surgery and improved HRQOL in children with drug-resistant epilepsy. However, child and parent depressive symptoms and family resources were not significant mediators. The results highlight the importance of achieving seizure control to improve HRQOL.

Trajectory of Health-Related Quality of Life After Pediatric Epilepsy Surgery.

Importance: Health-related quality of life (HRQOL) is regarded as a key outcome for evaluating treatment efficacy. However, it is uncertain how HRQOL evolves after epilepsy surgery compared with medical therapy, such as whether it continues to improve over time, improves and then remains stable, or deteriorates after a period of time. Objective: To assess trajectory of HRQOL over 2 years in children with drug-resistant epilepsy (DRE) treated with surgery compared with medical therapy. Design, Setting, and Participants: Prospective cohort study assessing HRQOL longitudinally over 2 years. Participants were children recruited from 8 epilepsy centers in Canada from 2014 to 2019 with suspected DRE aged 4 to 18 years who were evaluated for surgery. Data were analyzed from May 2014 to December 2021. Exposures: Epilepsy surgery or medical therapy. Main Outcomes and Measures: HRQOL was measured using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE)-55. HRQOL and seizure frequency were assessed at baseline, 6-month, 1-year, and 2-year follow-ups. Clinical, parent, and family characteristics were assessed at baseline. A linear mixed model was used to evaluate HRQOL over time, adjusting for baseline clinical, parent, and family characteristics. Results: There were 111 surgical and 154 medical patients (mean [SD] age at baseline was 11.0 [4.1] years; 118 [45%] were female). At baseline, HRQOL was similar among surgical and medical patients. HRQOL of surgical patients was 3.0 (95% CI, -0.7 to 6.8) points higher at 6-month, 4.9 (95% CI, 0.7 to 9.1) points higher at 1-year, and 5.1 (95% CI, 0.7 to 9.5) points higher at 2-year follow-ups compared with medical patients. Surgical patients experienced greater improvements in social functioning relative to medical patients, but not for cognitive, emotional, and physical functioning. At 2-year follow-up, 72% of surgical patients were seizure-free, compared with 33% of medical patients. Seizure-free patients reported higher HRQOL than those who were not. Conclusions and Relevance: This study provided evidence on the association between epilepsy surgery and children's HRQOL, with improvement in HRQOL occurring within the first year and remaining stable 2 years after surgery. By demonstrating that surgery improved seizure freedom and HRQOL, which has downstream effects such as better educational attainment, reduced health care resource utilization, and health care cost, these findings suggest that the high costs of surgery are justified, and that improved access to epilepsy surgery is necessary.

Longitudinal changes in emotional functioning following pediatric resective epilepsy surgery: 2-Year follow-up.

OBJECTIVE: To examine longitudinal changes and predictors of depression and anxiety 2 years following resective epilepsy surgery, compared to no surgery, in children with drug-resistant epilepsy (DRE). METHOD: This multicenter cohort study involved 128 children and adolescents with DRE (48 surgical, 80 nonsurgical; 8-18 years) who completed self-report measures of depression and anxiety at baseline and follow-up (6-month, 1-year, 2-year). Child demographic (age, sex, IQ) and seizure (age at onset, duration, frequency, site and side) variables were collected. RESULTS: Linear mixed-effects models controlling for age at enrolment found a time by treatment by seizure outcome interaction for depression. A negative linear trend across time (reduction in symptoms) was found for surgical patients, irrespective of seizure outcome. In contrast, the linear trend differed depending on seizure outcome in nonsurgical patients; a negative trend was found for those with continued seizures, whereas a positive trend (increase in symptoms) was found for those who achieved seizure freedom. Only a main effect of time was found for anxiety indicating a reduction in symptoms across patient groups. Multivariate regressions failed to find baseline predictors of depression or anxiety at 2-year follow-up in surgical patients. Older age, not baseline anxiety or depression, predicted greater symptoms of anxiety and depression at 2-year follow-up in nonsurgical patients. CONCLUSION: Children with DRE reported improvement in anxiety and depression, irrespective of whether they achieve seizure control, across the 2 years following surgery. In contrast, children with DRE who did not undergo surgery, but achieved seizure freedom, reported worsening of depressive symptoms, which may indicate difficulty adjusting to life without seizures and highlight the potential need for ongoing medical and psychosocial follow-up and support.

Distinct patterns of repetition suppression in Fragile X syndrome, down syndrome, tuberous sclerosis complex and mutations in SYNGAP1.

Sensory processing is the gateway to information processing and more complex processes such as learning. Alterations in sensory processing is a common phenotype of many genetic syndromes associated with intellectual disability (ID). It is currently unknown whether sensory processing alterations converge or diverge on brain responses between syndromes. Here, we compare for the first time four genetic conditions with ID using the same basic sensory learning paradigm. One hundred and five participants, aged between 3 and 30 years old, composing four clinical ID groups and one control group, were recruited: Fragile X syndrome (FXS; n = 14), tuberous sclerosis complex (TSC; n = 9), Down syndrome (DS; n = 19), SYNGAP1 mutations (n = 8) and Neurotypical controls (NT; n = 55)). All groups included female and male participants. Brain responses were recorded using electroencephalography (EEG) during an audio-visual task that involved three repetitions of the pronunciation of the phoneme /a/. Event Related Potentials (ERP) were used to: 1) compare peak-to-peak amplitudes between groups, 2) evaluate the presence of repetition suppression within each group and 3) compare the relative repetition suppression between groups. Our results revealed larger overall amplitudes in FXS. A repetition suppression (RS) pattern was found in the NT group, FXS and DS, suggesting spared repetition suppression in a multimodal task in these two ID syndromes. Interestingly, FXS presented a stronger RS on one peak-to-peak value in comparison with the NT. The results of our study reveal the distinctiveness of ERP and RS brain responses in ID syndromes. Further studies should be conducted to understand the molecular mechanisms involved in these patterns of responses.

A case report of severe tuberous sclerosis complex detected in utero and linked to a novel duplication in the TSC2 gene.

BACKGROUND: Disease severity is tremendously variable in tuberous sclerosis complex (TSC). In contrast with the detailed guidelines available for TSC diagnosis and management, clinical practice lacks adequate tools to evaluate the prognosis, especially in the case of in utero diagnosis. In addition, the correlation between genotypes and phenotypes remains a challenge, in part due to the large number of mutations linked to TSC. In this report, we describe a case of severe TSC diagnosed in utero and associated with a specific mutation in the gene tuberous sclerosis complex 2 (TSC2). CASE PRESENTATION: A mother was referred for a thorough investigation following the observation by ultrasound of cardiac abnormalities in her fetus. The mother was healthy and reported frequent, intense and long-lasting hiccups/spasms in the fetus. The fetus of gestational age 33 weeks and 4 days was found to have multiple cardiac tumors with cardiac ultrasound. Brain magnetic resonance imaging (MRI) performed in utero revealed the presence of sub-ependymal nodules and of abnormal signals disseminated in the white matter, in the cerebral cortex and in the cerebellum. Following diagnosis of definite TSC, pregnancy interruption was chosen by the parents. Genetic testing of the fetus exposed a duplication in exon 41 of TSC2 (c.5169dupA), which was absent in the parents. The autopsy ascertained the high severity of brain damage characterized by an extensive disorganisation of white and grey matter in most cerebral lobes. CONCLUSIONS: This case presentation is the first to depict the association between a de novo TSC2 c.5169dupA and multi-organ manifestation together with indications of a particularly high disease severity. This report can help physicians to perform early clinical diagnosis of TSC and to evaluate the prognosis.

Accelerated Cardiac Rhabdomyoma Regression with Everolimus in Infants with Tuberous Sclerosis Complex.

Tuberous sclerosis complex is associated with benign tumors such as cardiac rhabdomyomas (RHM) caused by the disinhibition of the mammalian target of rapamycin (mTOR) protein. Recent reports on everolimus, an mTOR inhibitor, have shown size reduction of RHM. We compared cases recently treated with everolimus to historic controls whose first echocardiography was within first month of life. The largest dimension of the largest RHM was reported as a percentage compared to the earliest echocardiography study. Treatment of the four cases was started at a median age of 6.5 days (range 2-20) with an initial enteral dose of 0.1 mg daily, aiming at a therapeutic serum trough level of 5-15 ng/mL. Median duration of everolimus treatment was 73 days (range 34-138). Compared to 10 historic controls, everolimus-treated patients had 11.8 times faster RHM size regression rate (slope -0.0285 vs. -0.0024; p < 0.001). The average time to 50% size reduction was 1.13 ± 0.33 month (range 0.66-1.4 months) with everolimus versus 72.9 ± 53.03 months in controls (p = 0.026). Following treatment with everolimus, one case was operated for congenital heart disease, without requirement of RHM resection, two others had the massive left ventricle RHM shrink to non-consequential size. The latter had a disappearance of RHM, but everolimus therapy was maintained to prevent the regrowth of a significant cerebral tumor. Everolimus is efficacious for size reduction of RHM during the neonatal period. With limited safety data, this approach should be used with caution in selective cases.

Predictive Factors for Epilepsy in Pediatric Patients With Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber syndrome is characterized by a facial port-wine stain associated with either or both a retinal angioma and a cerebral pial angioma. Because a pial angioma may not be evident on the initial imaging studies, individuals at risk for epilepsy are often not identified before their first seizure. The aim of this study is to identify predictive factors predisposing Sturge-Weber patients to epilepsy. METHODS: The medical archives and photography database of our institution were reviewed to identify Sturge-Weber Syndrome patients followed up between 1990 and 2015. Patients without epilepsy were compared with patients with epilepsy based on the location of the port-wine stain, its extent and cerebral imaging. RESULTS: Twenty-four patients were included in the study. Thirteen did not develop epilepsy. Patients with bilateral port-wine stain were at higher risk of epilepsy (P = 0.03). Unilateral port-wine stain did not increase the risk of epilepsy (P = 0.29) regardless of its extent. The presence of developmental venous anomalies on brain imaging was also associated with a higher risk of epilepsy (P = 0.03). CONCLUSIONS: Bilateral facial port-wine stain and cerebral developmental venous anomalies increase the risk of epilepsy in Sturge-Weber syndrome patients. Because they can be detected at birth, they might guide preventive management and follow-up.

Structured assessment and followup for patients with hereditary kidney tumour syndromes.

INTRODUCTION: Optimal clinical assessment and subsequent followup of patients with or suspected of having a hereditary renal cell carcinoma syndrome (hRCC) is not standardized and practice varies widely. We propose protocols to optimize these processes in patients with hRCC to encourage a more uniform approach to management that can then be evaluated. METHODS: A review of the literature, including existing guidelines, was carried out for the years 1985-2015. Expert consensus was used to define recommendations for initial assessment and followup. RESULTS: Recommendations for newly diagnosed patients' assessment and optimal ages to initiate followup protocols for von Hippel Lindau disease (VHL), hereditary papillary renal cancer (HPRC), hereditary leiomyomatosis with renal cell carcinoma (HLRCC), Birt-Hogg-Dubé syndrome (BHD), familial paraganglioma-pheochromocytoma syndromes (PGL-PCC), and tuberous sclerosis (TSC) are proposed. CONCLUSIONS: Our proposed consensus for structured assessment and followup is intended as a roadmap for the care of patients with hRCC to guide healthcare providers. Although the list of syndromes included is not exhaustive, the document serves as a starting point for future updates.

Resective Epilepsy Surgery for Tuberous Sclerosis in Children: Determining Predictors of Seizure Outcomes in a Multicenter Retrospective Cohort Study.

BACKGROUND: There are no established variables that predict the success of curative resective epilepsy surgery in children with tuberous sclerosis complex (TSC). OBJECTIVE: We performed a multicenter observational study to identify preoperative factors associated with seizure outcome in children with TSC undergoing resective epilepsy surgery. METHODS: A retrospective chart review was performed in eligible children at New York Medical Center, Miami Children's Hospital, Cleveland Clinic Foundation, BC Children's Hospital, Hospital for Sick Children, and Sainte-Justine Hospital between January 2005 and December 2013. A time-to-event analysis was performed. The "event" was defined as seizures after resective epilepsy surgery. RESULTS: Seventy-four patients (41 male) were included. The median age of the patients at the time of surgery was 120 months (range, 3-216 months). The median time to seizure recurrence was 24.0 ± 12.7 months. Engel Class I outcome was achieved in 48 (65%) and 37 (50%) patients at 1- and 2-year follow-up, respectively. On univariate analyses, younger age at seizure onset (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.03-4.00, P = .04), larger size of predominant tuber (HR: 1.03, 95% CI: 0.99-1.06, P = .12), and resection larger than a tuberectomy (HR: 1.86, 95% CI: 0.92-3.74, P = .084) were associated with a longer duration of seizure freedom. In multivariate analyses, resection larger than a tuberectomy (HR: 2.90, 95% CI: 1.17-7.18, P = .022) was independently associated with a longer duration of seizure freedom. CONCLUSION: In this large consecutive cohort of children with TSC and medically intractable epilepsy, a greater extent of resection (more than just the tuber) is associated with a greater probability of seizure freedom. This suggests that the epileptogenic zone may include the cortex surrounding the presumed offending tuber.

Lymphangioleiomyomatosis and Tuberous Sclerosis Complex in Quebec: Prevalence and Health-care Utilization.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a manifestation of tuberous sclerosis complex (TSC) that causes destruction of the lung and chronic respiratory failure. Population-based estimates of demographics, clinical outcomes, and health-care utilization are lacking for TSC and LAM. METHODS: Data on demographics, clinical outcomes, and health-care utilization in the Quebec ministerial provincial health-care database were analyzed for their association with TSC and LAM. RESULTS: A total of 1,004 subjects with TSC were identified using International Classification of Diseases, Ninth and 10th Revisions, codes for a prevalence of one in 7,872 people. There were 38 subjects with LAM, nine of whom also had TSC. Mean ages as well as the mean age at death were lower in the LAM and TSC group than in the control group. Mortality rates were higher in subjects with LAM than in those with TSC or in control subjects. Subjects with LAM experienced more medical visits and hospitalizations than did those with TSC and control subjects; these were associated with higher health-care costs. Frequently prescribed drugs in TSC or LAM included anticonvulsants, antidepressants, and sedatives; the use of mammalian target of rapamycin inhibitors was uncommon. CONCLUSIONS: The prevalence of TSC in Quebec, Canada, is similar to estimates from previously published surveys. LAM is likely underreported, perhaps due to suboptimal case identification or referral. Health-care utilization and mortality for LAM are high, suggesting that timely diagnosis and therapy could be beneficial. Mental health disorders may be an unrecognized clinical feature of LAM. These results provide a population-based background for policymakers and researchers to better address the needs of patients with TSC and LAM.

Use of mTOR inhibitor everolimus in three neonates for treatment of tumors associated with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex is characterized by the growth of benign tumors in multiple organs, caused by the disinhibition of the mammalian target of rapamycin (mTOR) protein. mTOR inhibitors, such as everolimus, are used in patients with tuberous sclerosis complex, mainly to reduce the size of renal angiomyolipomas and subependymal giant cell astrocytomas. There are minimal data available regarding its use during the neonatal period. METHODS: We report clinical and pharmacological data of three neonates treated with the mTOR inhibitor everolimus (two hemodynamically significant cardiac rhabdomyomas and one voluminous subependymal giant cell astrocytoma). RESULTS: Beneficial clinical responses were observed in all three patients and the medication was generally well-tolerated. Optimal dose was 0.1 mg orally once daily and was confirmed with therapeutic drug monitoring. CONCLUSION: Everolimus is a promising pharmacological approach to treat clinically significant inoperable cardiac rhabdomyomas or subependymal giant cell astrocytoma associated with tuberous sclerosis complex during the neonatal period.

Oral everolimus treatment in a preterm infant with multifocal inoperable cardiac rhabdomyoma associated with tuberous sclerosis complex and a structural heart defect.

Rhabdomyoma (RHM) is a benign cardiac tumour usually associated with tuberous sclerosis complex (TSC). Most RHMs are asymptomatic and regress spontaneously during the first years of life. Haemodynamically significant RHMs are classically treated with surgical excision. We present a case of a premature infant, born to a mother having TSC, with a prenatal diagnosis of pulmonary valve atresia and a large ventricular septal defect. Multiple cardiac RHMs were also present, including a large tumour affecting the right ventricular filling. Owing to the prematurity and low birth weight, the infant was inoperable. In this report, we describe our approach to pharmacologically reduce the RHM size using oral everolimus in preparation for a two-ventricle surgical repair of the structural cardiac defect. We also specifically describe the dose of everolimus that was used in this case to achieve therapeutic serum levels, which was seven times lower than the conventional dose applicable for older infants.

Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly.

BACKGROUND: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), a disorder characterised by the development of hamartomas or benign tumours in various organs as well as the variable presence of epilepsy, intellectual disability (ID) and autism. TSC1, TSC2 and the recently described protein TBC1D7 form a complex that inhibits mTORC1 signalling and limits cell growth. Although it has been proposed that mutations in TBC1D7 might also cause TSC, loss of its function has not yet been documented in humans. METHODS AND RESULTS: We used homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly but without any specific features of TSC. We identified only one rare coding variant, c.538delT:p.Y180fsX1 in TBC1D7, in the regions of homozygosity shared by the affected siblings. We show that this mutation abolishes TBC1D7 expression and is associated with increased mTORC1 signalling in cells of the affected individuals. CONCLUSIONS: Our study suggests that disruption of TBC1D7 causes ID but without the other typical features found in TSC. Although megalencephaly is not commonly observed in TSC, it has been associated with mTORC1 activation. Our observation thus reinforces the relationship between this pathway and the development of megalencephaly.

Potential of mTOR inhibitors for the treatment of subependymal giant cell astrocytomas in tuberous sclerosis complex.

Rapamycin inhibits the mTOR (target of rapamycin) pathway and extends lifespan in multiple species. The tuberous sclerosis complex (TSC) protein is a negative regulator of mTOR. In humans, loss of the TSC protein results in a disorder characterized clinically by the growth of benign tumors in multiple organs, due to overactivation of mTOR inhibition. Subependymal giant cell astrocytomas (SEGAs) are benign brain tumors associated with TSC that have traditionally been treated by surgery, but for which mTOR inhibitors have recently been suggested as potential alternative treatments. The duration of mTOR treatment for SEGAs might have to be prolonged, probably lifelong, because SEGAs usually grow back after treatment is stopped. This cohort of patients who will experience prolonged exposure to mTOR inhibitors should be carefully followed longitudinally to better document long term side effects, but also to compare their longevity with the one of similar patients with TSC. These patients represent a unique opportunity to study the potential anti-aging properties of mTOR inhibitors in humans.

Rapamycin as an alternative to surgical treatment of subependymal giant cell astrocytomas in a patient with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is associated with the potential development of benign hamartomas, including subependymal giant cell astrocytomas (SEGAs). Intracranial hypertension can be caused by SEGAs due to their propensity to block the foramen of Monro. The traditional management approach is to monitor SEGAs with periodic neuroimaging and to resect those that exhibit serial growth and/or cause clinical signs of intracranial hypertension. Recent observations suggest that rapamycin therapy may induce partial regression of SEGAs, therefore providing a potential alternative to resection. The authors present the case of an 8-year-old girl with bilateral SEGAs that led to progressive hydrocephaly and incipient signs of papilledema. Three months after initiating rapamycin therapy, the SEGAs exhibited significant reduction in size (82.6% on the left and 46.7% on the right), and the lesions remained stable 5 months later. Compared with previous case reports, similar or even greater antitumor efficacy was achieved with much lower trough levels of rapamycin (10–15 compared with 3.3–4.5 ng/ml, respectively). The authors discuss various aspects of rapamycin therapy and address unresolved issues that highlight the need for further prospective clinical trials.

The natural history of epilepsy in tuberous sclerosis complex.

BACKGROUND: Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease. METHODS: A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation. RESULTS: Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure; 54.1% developed multiple seizure types, not including IS; 63.2% had seizure onset in the first year of life; and 12.1% of adults without a seizure history developed epilepsy. Of epilepsy patients, 62.5% developed refractory epilepsy and 33.5% achieved epilepsy remission; 37.5% of these patients achieved medication freedom. IS was a risk factor for refractory epilepsy (p<0.0001) and LGS (p<0.0001). History of seizure, IS, age at seizure onset, and refractory epilepsy each correlated with poor cognitive outcome (p<0.0001). Epilepsy remission correlated with better cognitive outcome (p<0.0001). TSC2 was a risk factor for IS and epilepsy; patients without an identified mutation were more likely to achieve remission. CONCLUSION: Most patients with TSC develop epilepsy and most develop multiple seizure types. Onset typically occurs in the first year of life; however, adults remain at risk. Although refractory epilepsy is common, many patients achieve seizure control. Many features of seizure history are predictive of cognitive and epilepsy outcome.