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Subependymal giant cell astrocytoma (SEGA) is a rare, low‐grade glioma typically associated with tuberous sclerosis (TS) and mutations in the TSC1 or TSC2 genes. It is characterized by an intraventricular location, an expansive growth pattern, and the expression of glial and neural markers. TTF‐1 expression is considered a sensitive marker of SEGA, likely reflecting its origin from progenitor cells in the caudothalamic groove. We report a case of SEGA with unusual immunohistochemical and molecular features in a 20‐year‐old man with no signs or family history of TS. The tumor was located in the anterior horn of the right ventricle and obstructed the foramen of Monro. Histologically, it exhibited an expansive growth pattern and was composed of cells with ovoid nuclei and abundant eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for GFAP and S‐100 protein, weakly positive for SOX2, focally positive for synaptophysin, and negative for TTF‐1, neurofilament protein, NeuN, EMA, chromogranin, and BCOR. Scattered OLIG2‐positive neoplastic cells were also observed. Molecular analysis revealed no pathogenic mutations or copy number variations in the analyzed 174 genes, including TSC1/2, except for a variant of unknown significance in BAP1. The histopathological features and immunohistochemical profile suggested SEGA, despite the absence of TTF‐1 expression and TSC1/2 mutations. The diagnosis was confirmed by DNA methylation profiling, which assigned the tumor to the methylation class “subependymal giant cell astrocytoma with TSC1/TSC2 alterations” with a calibrated score of 0.95. This case highlights the potential diagnostic pitfall of SEGA lacking TTF‐1 expression and emphasizes the importance of considering this entity in the differential diagnosis of intraventricular tumors, even in the absence of TS and characteristic molecular alterations. The existence of TTF‐1 negative SEGAs reveals that these tumors might also derive from TTF‐1 negative cells in the subpendymal region. [ABSTRACT FROM AUTHOR]

Simple Summary: Subependymal giant cell astrocytoma is a slow-growing brain tumor affecting children and young adults. Despite the characteristic molecular and clinical features, the severity of the disease varies from patient to patient, and, in addition, tumors in their early stages can be asymptomatic for a long time. Morbidity and mortality are due to the location of the tumor, which can obstruct the flow of cerebrospinal fluid, leading to progressive hydrocephalus and even death. The etiology and the response to treatment are still poorly understood due to the diversity of the background and the course of the disease. Therefore, this review aims to present and discuss the latest research on SEGA, its diagnosis, and treatment. Subependymal giant cell astrocytoma (SEGA) is most often found in patients with TSC (Tuberous Sclerosis Complex). Although it has been classified as a benign tumor, it may create a serious medical problem leading to grave consequences, including young patient demise. Surgery and chemotherapy belong to the gold standard of treatment. A broader pharmacological approach involves the ever-growing number of rapalogs and ATP-competitive inhibitors, as well as compounds targeting other kinases, such as dual PI3K/mTOR inhibitors and CK2 kinase inhibitors. Novel approaches may utilize noncoding RNA-based therapeutics and are extensively investigated to this end. The purpose of our review was to characterize SEGA and discuss the latest trends in the diagnosis and therapy of this disease. [ABSTRACT FROM AUTHOR]

Abstract Background Subependymal giant cell astrocytoma is a benign brain tumor that occurs in patients with tuberous sclerosis complex. Surgical removal is the traditional treatment, and expert opinion is strongly against the use of radiotherapy. Recently, success has been reported with the mTor inhibitor everolimus in reducing tumor volume, but regrowth has been observed after dose reduction or cessation. Case report We present the case of a 40-year-old Asian female patient treated successfully for growing bilateral subependymal giant cell astrocytoma with fractionated stereotactic radiotherapy before everolimus became available. After a follow-up of 8 years, everolimus was administered for renal angiomyolipoma and the patient was followed up until 13 years after radiotherapy. Successive magnetic resonance imaging demonstrated an 80% volume reduction after radiotherapy that increased to 90% with everolimus. A review of the literature was done leveraging Medline via PubMed, and we assembled a database of 1298 article references and 780 full-text articles in search of evidence for contraindicating radiotherapy in subependymal giant cell astrocytoma. Varying results of single-fraction radiosurgery were described in a total of 13 cases. Only in two published cases was the radiation dose of fractionated radiotherapy mentioned. One single publication mentions an induced secondary brain tumor 8 years after whole-brain radiotherapy. Conclusion There is no evidence of contraindication and exclusion of fractionated radiotherapy in treating subependymal giant cell astrocytoma. Our experience demonstrates that subependymal giant cell astrocytoma, as other benign intracranial tumors, responds slowly but progressively to radiotherapy and suggests that fractionated stereotactic radiotherapy holds promise to consolidate responses obtained with mTor inhibitors avoiding regrowth after cessation.

Background: Subependymal giant cell astrocytoma is a benign brain tumor that occurs in patients with tuberous sclerosis complex. Surgical removal is the traditional treatment, and expert opinion is strongly against the use of radiotherapy. Recently, success has been reported with the mTor inhibitor everolimus in reducing tumor volume, but regrowth has been observed after dose reduction or cessation. Case report: We present the case of a 40-year-old Asian female patient treated successfully for growing bilateral subependymal giant cell astrocytoma with fractionated stereotactic radiotherapy before everolimus became available. After a follow-up of 8 years, everolimus was administered for renal angiomyolipoma and the patient was followed up until 13 years after radiotherapy. Successive magnetic resonance imaging demonstrated an 80% volume reduction after radiotherapy that increased to 90% with everolimus. A review of the literature was done leveraging Medline via PubMed, and we assembled a database of 1298 article references and 780 full-text articles in search of evidence for contraindicating radiotherapy in subependymal giant cell astrocytoma. Varying results of single-fraction radiosurgery were described in a total of 13 cases. Only in two published cases was the radiation dose of fractionated radiotherapy mentioned. One single publication mentions an induced secondary brain tumor 8 years after whole-brain radiotherapy. Conclusion: There is no evidence of contraindication and exclusion of fractionated radiotherapy in treating subependymal giant cell astrocytoma. Our experience demonstrates that subependymal giant cell astrocytoma, as other benign intracranial tumors, responds slowly but progressively to radiotherapy and suggests that fractionated stereotactic radiotherapy holds promise to consolidate responses obtained with mTor inhibitors avoiding regrowth after cessation. [ABSTRACT FROM AUTHOR]

Objective: To compare clinicopathological characteristics of patients with solitary subependymal giant cell astrocytoma (SEGA) at our institution, with those associated to tuberous sclerosis complex (TSC). Methods: It was a descriptive-retrospective study of surgically treated SEGA patients (2013-2022). Demographic and clinical data were obtained. An immunohistochemistry (IHC) panel was applied: GFAP, neurofilaments, hamartin, tuberin, Ki67, nestin, OCT-4, INI-1, STAT-6, CK-AE1/ AE3, TTF1, and YAP-1. Descriptive statistical was used. Results: 4 patients were studied: Two women, 23 and 25 years old, diagnosed as TSC patients at 10 and 12 years of age, and two men with solitary SEGA (18 and 46 years old). Tumors were positive to GFAP, NF, nestin, and TTF1. Cytoplasmic STAT6 and CK stains was observed in all patients. 2/4 cases showed YAP-1 nuclear expression. TSC patients retained INI-1 nuclear expression, while solitary SEGAs lost it. Conclusions: SEGA is a glioneuronal tumor that expresses markers of neuroepithelial stem cells and cytokeratins. Its diagnosis must be supported with a minimal IHC panel: GFAP, neurofilaments, synaptophysin, nestin and TTF1. Morphological differences were observed between the TSC related and solitary SEGAs and in INI1 expression. Nuclear expression of YAP-1 in 2/4 tumors, opens the possibility of research for combined use of YAP and mTOR regulators in the management of SEGA. [ABSTRACT FROM AUTHOR]

Abstract Background A case of tuberous sclerosis patient on long-term follow-up is reported here. Case presentation A 22-year-old female patient with epilepsy was diagnosed with tuberous sclerosis at the age of 12 years. At that time, a small subependymal giant cell astrocytoma has been detected along with the other signs of the disease. But the patient was not symptomatic of the intracranial lesion at that time. So, she was kept under follow-up with treatment for the epilepsy. Within 10 years, the lesion gradually enlarged and caused symptoms and the tumour had to be resected at the age of 22 years of age. Conclusions Subependymal giant cell astrocytoma is very slow-growing low-grade tumour. If small and asymptomatic at the time of the initial diagnosis, resection is not advised. The patient should be kept under close follow-up.

Abstract Background The randomised double-blinded placebo-controlled EXIST-1–3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. Results The study included 64 patients with TSC (median age: 19, range 0.9–54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients

Background: A case of tuberous sclerosis patient on long-term follow-up is reported here. Case presentation: A 22-year-old female patient with epilepsy was diagnosed with tuberous sclerosis at the age of 12 years. At that time, a small subependymal giant cell astrocytoma has been detected along with the other signs of the disease. But the patient was not symptomatic of the intracranial lesion at that time. So, she was kept under follow-up with treatment for the epilepsy. Within 10 years, the lesion gradually enlarged and caused symptoms and the tumour had to be resected at the age of 22 years of age. Conclusions: Subependymal giant cell astrocytoma is very slow-growing low-grade tumour. If small and asymptomatic at the time of the initial diagnosis, resection is not advised. The patient should be kept under close follow-up. [ABSTRACT FROM AUTHOR]

Background: The randomised double-blinded placebo-controlled EXIST-1–3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. Results: The study included 64 patients with TSC (median age: 19, range 0.9–54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0–106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3–4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. Conclusions: Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects. [ABSTRACT FROM AUTHOR]

Introduction: Everolimus is the primary therapeutic option for patients with tuberous sclerosis complex (TSC) and subependymal giant astrocytoma (SEGA). This study aimed to assess the effect of everolimus, a mammalian-target- -of-rapamycin (mTOR) inhibitor, on complete blood count (CBC) parameters in patients with TSC and SEGA. Material and methods: The study included 18 pediatric patients with TSC-associated SEGA tumors as indications for everolimus treatment. During the standard dose therapy and maintenance phase (<50% of standard dose), CBC results and everolimus whole blood concentrations were collected at five study time points. Results: Everolimus contributed to decreasing almost all blood cell values. The most severe toxicity occurred six months after therapy commenced. Dose reduction resulted in slightly normalizing parameters, but they did not return to the initial ones in all cases. During the study, only a few instances of cytopenia were reported. The most common abnormality was granulocytopenia, observed in one in three patients. Almost all cytopenias occurred during the standard treatment phase, and none were classified as severe. Hematological toxicity was not the reason for therapy interruption or withdrawal. Conclusions: A decrease in almost all hematological parameters is widespread during everolimus therapy. Hematological toxicities are rare and mild. The unique abnormality for mTOR inhibitors is microcytosis. Reduction of mTOR inhibitor dose results in a lower frequency of hematological side effects. [ABSTRACT FROM AUTHOR]

Introduction: Subependymal giant cell astrocytoma (SEGA) is the most common CNS tumor in patients with tuberous sclerosis complex (TSC). Although these are benign, their proximity to the foramen of Monroe frequently causes obstructive hydrocephalus, a potentially fatal complication. Open surgical resection has been the mainstay of treatment; however, this can cause significant morbidity. The development of mTOR inhibitors has changed the treatment landscape, but there are limitations to their use. Laser interstitial thermal therapy (LITT) is an emerging treatment modality that has shown promise in treatment of a variety of intracranial lesions, including SEGAs. We present a single institution, retrospective study of patients treated for SEGAs with LITT, open resection, mTOR inhibitors, or a combination of these modalities. The primary study outcome was tumor volume at most recent follow-up compared with volume at treatment initiation. The secondary outcome was clinical complications associated with treatment modality. Methods: Retrospective chart review was performed to identify patients with SEGAs treated at our institution from 2010 to 2021. Demographics, treatment information, and complications were collected from the medical record. Tumor volumes were calculated from imaging obtained at initiation of treatment and at most recent follow-up. Kruskal-Wallis nonparametric testing was used to assess differences in tumor volume and follow-up duration between groups. Results: Four patients underwent LITT (3 with LITT only), three underwent open surgical resection, and four were treated with mTOR inhibitors only. Mean percent tumor volume reduction for each group was 48.6 ± 13.8, 90.7 ± 39.8, and 67.1 ± 17.2%, respectively. No statistically significant difference was identified comparing percent tumor volume reduction between the three groups (p = 0.0513). Additionally, there was no statistically significant difference in follow-up duration between groups (p = 0.223). Only 1 patient in our series required permanent CSF diversion and 4 discontinued or decreased the dose of mTOR inhibitor due to either cost or side effects. Conclusions: Our study suggests that LITT could be considered as a treatment option for SEGAs as it was effective in reducing tumor volume with very few complications. This modality is less invasive than open resection and may be an alternative for patients who are not candidates for mTOR inhibitors. We recommend an updated paradigm for SEGA treatment which includes LITT in select cases after consideration of patient-specific factors. [ABSTRACT FROM AUTHOR]

The newest revision of the WHO classification of tumors of the central nervous system, also known as WHO 5th edition, introduces substantial changes, especially within the glial tumor category and separates adult-type and pediatric-type glial tumors into different categories for the first time. In addition, another category of glial tumors, “Circumscribed Astrocytic Gliomas” were also created. This group includes pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, astroblastoma, and the highly nebulous novel entity high-grade astrocytoma with piloid features. We present a brief and critical review of the pathological and molecular characteristics of these often well-demarcated tumors that can occur in adults as well as in the pediatric population.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by widespread clinical manifestations. Early diagnosis is usually possible when typical TSC related skin lesions and neurologic presentations are detected in young patients. Undiagnosed TSC patients are at increased risk of morbidity and mortality as disease progression will inevitably lead to complications. While case reports of single complications in pediatric patients have been documented, to the best of our knowledge, multi-system complications of TSC in adults have yet to be reported in the literature. We present a case of tuberous sclerosis diagnosed in adulthood with complications involving the central nervous, renal and respiratory systems. This case highlights the need for a multidisciplinary approach in the management of TSC as well as the role of imaging in both diagnosis and intervention.

Subependymal Giant Cell Astrocytoma (SEGA) is a common diagnosis in patients with Tuberous Sclerosis. Although surgical treatment is often required, resection may entail a significant risk for cognitive function given the anatomical relation with critical structures such as the fornices and subgenual area. Therefore, target subtotal resections using minimal invasive approaches focused in the higher metabolic areas are valuable options to preserve quality of life while addressing specific problems caused by the tumor, such as hydrocephalus or progressive growth of a specific component of the tumor. In this report, the authors explore the potential role of 5-ALA in the identification of highly metabolic areas during SEGA resection in the context of minimal invasive approaches.

Abstract Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC. Methods A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019). Results We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18–78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533–7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780–1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503–3840) among working-age individuals (

Tuberous sclerosis complex (TSC) is a rare genetic disease that is inherited autosomal dominantly and may be associated with subependymal giant cell astrocytoma (SEGA) in 10-20% of cases. Different phenotypes are related to the form of lesions in different parts of the body, including skin, brain, kidneys, lungs, and heart. The age of the patient, the location of the tumor, and associated skin or neurological lesions may guide the pathologist for a definite diagnosis. Here we report a case of SEGA in an adolescent with TSC. Neurological clues including seizure and mental retardation, facial angiofibroma, renal mass, and histopathology examination of the brain tumor culminated in the diagnosis of TSC and SEGA. [ABSTRACT FROM AUTHOR]

Abstract Objective Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions. Methods A 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the clinical data of the patient. We performed biopsy of cutaneous nodules and whole-exome sequencing in both paraffin block tissue and blood samples. Results The patient presented with a 2 month history of gradual growth multiple cutaneous nodules. He had cardiac rhabdomyoma, subependymal giant cell astrocytoma (SEGA) and hypomelanotic macules. The pathological finding of cutaneous nodules was consistent with juvenile xanthogranuloma (JXG). After 3 months of sirolimus treatment, the multiple nodules disappeared. The whole-exome sequencing identified TSC1 (c.2356C > T, p.R786*) mutation in both paraffin block tissue and blood samples. We overturned the original pathological diagnosis and finally identified JXG as a new type of skin lesions in TSC. Conclusion This is the first report on the occurrence of JXG skin lesions in TSC patient. Genetic testing is necessary in JXG. These findings expand the phenotype of skin in patients with TSC and contribute to the elucidation of JXG pathogenesis and treatment.

Background: There is limited literature on the use of positron emission tomography (PET) for benign tumors originating in the brain ventricles, and the use of multiple tracers for subependymal giant cell astrocytoma (SEGA) has not been reported. The authors compared the PET findings in two SEGA cases with past reports and literature, exploring the distinctive characteristics of SEGA on PET., Observations: In a 21-year-old female with SEGA, the authors utilized 18F-fluorodeoxyglucose (18F-FDG), 11C-methionine (11C-MET), 18F-fluorothymidine (18F-FLT), 18F-fluoromisonidazole, and 18F-THK5351 tracers. Additionally, in a 6-year-old girl, the authors performed 11C-MET PET., Lessons: The results indicated the accumulation of all tracers except 18F-FDG, with particularly intense accumulation noted with 18F-FLT. In particular, 18F-FLT demonstrated accumulation comparable to that observed in malignant tumors. This study suggests that multiple PET tracers can provide valuable insights into the characterization of SEGA, with 18F-FLT showing particular promise as a distinctive marker of blood-brain barrier disruption. Further research in larger cohorts may enhance our understanding of metabolic patterns in SEGA and aid in its diagnosis and treatment. https://thejns.org/doi/10.3171/CASE24111.

Objective Subependymal Giant Cell Astrocytomas (SEGAs) are slow-growing glioneuronal tumors typically found around the ventricles of the brain, particularly near the foramen of Monro in 15%-20% of patients with tuberous sclerosis complex (TSC). Surgical resection is the standard treatment for these symptomatic tumors. The mTOR inhibitor everolimus can be regarded as an alternative treatment for SEGAs due to the complications of surgery. The present study primarily aimed to specify the effect of everolimus on SEGA volume change before and after treatment. The secondary objective was to determine the effect of this drug on renal angiomyolipoma (AML), skin lesions, and seizures in TSC patients. Materials & Methods This pre- and post-treatment clinical trial was performed on 14 children (eight females and six males with a mean age of 10 years) previously diagnosed with TSC based on the diagnostic criteria. The subjects received oral everolimus at a dose of 3 mg/m² for at least six months. Results Half of the patients had more than 30% of volume loss in SEGA, and in 28.5% of them, a ≥ 50% reduction in SEGA volume was observed (P=0.01). Moreover, 92.9% of the patients had a ≥ 50% decrease in the frequency of seizures (P=0.000). The response rate in AML and skin lesions was 14.2% and 50%, respectively. Conclusion Everolimus significantly reduced the seizure frequency and SEGA volume in the subjects; hence, it can be used as a potential alternative treatment for symptomatic SEGA in TSC patients. [ABSTRACT FROM AUTHOR]

Background: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC.Methods: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019).Results: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18-78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533-7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780-1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503-3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs.Conclusions: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting.Trial Registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045 . [ABSTRACT FROM AUTHOR]

The aim of this EMINENTS prospective, single-center, open-label, single-arm study was to evaluate the cumulative efficacy and safety of reduced doses of everolimus (maintenance therapy) in patients with tuberous sclerosis and subependymal giant cell astrocytoma (SEGA).Methods: The trial included 15 patients who had undergone at least 12 months of treatment with a standard everolimus dose. The dose of everolimus was reduced to three times a week, with a daily dose as in standard regimen. Data of 14 patients were analyzed. SEGA volume (SV) was evaluated at study entry and subsequent time points by an experienced radiologist. Adverse events (AEs) noted during maintenance therapy were compared to the AEs of standard dose period.Results: Patients were followed over a mean duration 58.37 months (95%CI: 45.95–70.78). The differences in SEGA volume between subsequent time points (0, 3, 6,12, 18, 24, 36, 48, and 60 months) were not statistically significant (p = 0.16). At the end of the study, 7 out of 10 patients had stable SEGA volume. No clinical symptoms of progression were observed in any patients. No patient or tumor-related risk factors of progression were identified. Regarding AEs, infections (stomatitis, bronchitis, diarrhea) and laboratory abnormalities (neutropenia, anemia, hyperglycemia) occurred less frequently during maintenance therapy compared to the standard dose regimen.Conclusions: Final results from EMINENTS study confirm that maintenance therapy with everolimus might represent a rational therapeutic option for patients TSC and SEGA after effective full dose treatment. It could be an option for patients who experienced everolimus-related AEs, instead of discontinuation of therapy. Careful evaluation of possible progression, especially concerning first six months of maintenance therapy should be advised.Clinical Trial Registration:www.drks.de, identifier DRKS00005584.

The aim of this EMINENTS prospective, single-center, open-label, single-arm study was to evaluate the cumulative efficacy and safety of reduced doses of everolimus (maintenance therapy) in patients with tuberous sclerosis and subependymal giant cell astrocytoma (SEGA). Methods: The trial included 15 patients who had undergone at least 12 months of treatment with a standard everolimus dose. The dose of everolimus was reduced to three times a week, with a daily dose as in standard regimen. Data of 14 patients were analyzed. SEGA volume (SV) was evaluated at study entry and subsequent time points by an experienced radiologist. Adverse events (AEs) noted during maintenance therapy were compared to the AEs of standard dose period. Results: Patients were followed over a mean duration 58.37 months (95%CI: 45.95–70.78). The differences in SEGA volume between subsequent time points (0, 3, 6,12, 18, 24, 36, 48, and 60 months) were not statistically significant (p = 0.16). At the end of the study, 7 out of 10 patients had stable SEGA volume. No clinical symptoms of progression were observed in any patients. No patient or tumor-related risk factors of progression were identified. Regarding AEs, infections (stomatitis, bronchitis, diarrhea) and laboratory abnormalities (neutropenia, anemia, hyperglycemia) occurred less frequently during maintenance therapy compared to the standard dose regimen. Conclusions: Final results from EMINENTS study confirm that maintenance therapy with everolimus might represent a rational therapeutic option for patients TSC and SEGA after effective full dose treatment. It could be an option for patients who experienced everolimus-related AEs, instead of discontinuation of therapy. Careful evaluation of possible progression, especially concerning first six months of maintenance therapy should be advised. Clinical Trial Registration: www.drks.de, identifier DRKS00005584. [ABSTRACT FROM AUTHOR]

Subependymal giant cell astrocytoma (SEGA) is a World Health Organization (WHO) grade I tumor most commonly seen in the context of the underlying tuberous sclerosis complex (TSC). SEGA in the absence of TSC is exceedingly rare. We report the youngest known case of SEGA in the absence of genetic or phenotypic evidence of TSC with a 10-year follow-up. We discuss the literature surrounding isolated SEGA including an approach to diagnosis, management, and prognosis. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a model disorder for understanding brain development because the genes that cause TSC are known, many downstream molecular pathways have been identified, and the resulting perturbations of cellular events are established. TSC, therefore, provides an intellectual framework to understand the molecular and biochemical pathways that orchestrate normal brain development. The TSC1 and TSC2 genes encode Hamartin and Tuberin which form a GTPase activating protein (GAP) complex. Inactivating mutations in TSC genes (TSC1/TSC2) cause sustained Ras homologue enriched in brain (RHEB) activation of the mammalian isoform of the target of rapamycin complex 1 (mTORC1). TOR is a protein kinase that regulates cell size in many organisms throughout nature. mTORC1 inhibits catabolic processes including autophagy and activates anabolic processes including mRNA translation. mTORC1 regulation is achieved through two main upstream mechanisms. The first mechanism is regulation by growth factor signaling. The second mechanism is regulation by amino acids. Gene mutations that cause too much or too little mTORC1 activity lead to a spectrum of neuroanatomical changes ranging from altered brain size (micro and macrocephaly) to cortical malformations to Type I neoplasias. Because somatic mutations often underlie these changes, the timing, and location of mutation results in focal brain malformations. These mutations, therefore, provide gain-of-function and loss-of-function changes that are a powerful tool to assess the events that have gone awry during development and to determine their functional physiological consequences. Knowledge about the TSC-mTORC1 pathway has allowed scientists to predict which upstream and downstream mutations should cause commensurate neuroanatomical changes. Indeed, many of these predictions have now been clinically validated. A description of clinical imaging and histochemical findings is provided in relation to laboratory models of TSC that will allow the reader to appreciate how human pathology can provide an understanding of the fundamental mechanisms of development.

Purpose: Subependymal giant cell astrocytomas (SEGAs) are rare tumors typically found in tuberous sclerosis patients. They typically grow in the region of the foramen of Monro and can occlude it, leading to hydrocephalus. Currently, gross total resection is the standard of care, with low rates of recurrence but high rates of complication, especially with larger lesions. Laser interstitial thermal therapy (LITT) is a newly emerging treatment modality for a variety of pathologies. Here, we present a case series of SEGAs managed via LITT and endoscopic, stereotactic septostomy. Methods: A retrospective chart review was performed to identify three cases in which SEGAs were treated via LITT and septostomy. Stereotactic ablation was performed via magnetic resonance (MR) thermometry with laser output set to 69% for 2.5 min, with post-ablation scans for visualization of treatment area. Results: Average age at surgery was 8.2 years. Pre-operative tumor volumes were 0.43, 1.51, and 3.88 cm3. Post-operative tumor volumes were 0.25, 0.21, and 0.68 cm3. Mean tumor volume reduction was 70%. No complications occurred. Conclusion: LITT with septostomy should be considered a viable primary or adjunct treatment modality for SEGAs. [ABSTRACT FROM AUTHOR]

Background: Subependymal giant cell astrocytomas (SEGAs) arise in 10-26% of tuberous sclerosis complex (TSC) patients. SEGAs cause obstructive hydrocephalus and increase morbi-mortality. It is recommended that TSC patients be followed with contrast enhanced magnetic resonance imaging (CE-MRI), but repetitive use of gadolinium-based contrast-agents (GBCAs) may cause organ deposits.Objective: To compare the diagnostic performances of non-CE- and CE-MRI to differentiate SEGAs from subependymal nodules in TSC patients during follow-up.Materials and Methods: Thirty-five TSC patients (median age: 2.4 years) were enrolled in this retrospective single-center study from September 2007 to January 2019. Inclusion criteria were a certain diagnosis of TSC and at least three follow-up brain MRIs with GBCA injection. Two consecutive MRI scans per patient were selected and anonymized. Three radiologists performed a blinded review of non-enhanced and enhanced MRI sequences during different sessions. The diagnostic performances were compared (sensitivity, specificity, positive/negative predictive values, accuracy, inter/intra-observer agreements).Results: The accuracies for detecting SEGAs were good and similar between the non-enhanced and enhanced MRI sequences. The sensitivity and specificity of non-CE-MRI to diagnose SEGA ranged from 75% to 100% and from 94% to 100%, respectively. The differences in numbers of false-positive and false-negative patients between non-CE- and CE-MRI never exceeded one case. Nodules size >10 mm, location near the Monro foramen, hydrocephalus and modifications between two consecutive MRI scans were significantly associated with the diagnosis of SEGA for the three readers (all P-values <0.05). Inter- and intra-observer agreements were also excellent for non-enhanced and enhanced MRI sequences (kappa=0.85-1 and 0.81-0.93, respectively).Conclusion: The performances of non-enhanced and enhanced MRI sequences are comparable for detecting SEGAs, questioning the need for systematic GBCA injections for TSC patients. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a model disorder for understanding brain development because the genes that cause TSC are known, many downstream molecular pathways have been identified, and the resulting perturbations of cellular events are established. TSC, therefore, provides an intellectual framework to understand the molecular and biochemical pathways that orchestrate normal brain development. The TSC1 and TSC2 genes encode Hamartin and Tuberin which form a GTPase activating protein (GAP) complex. Inactivating mutations in TSC genes (TSC1/TSC2) cause sustained Ras homologue enriched in brain (RHEB) activation of the mammalian isoform of the target of rapamycin complex 1 (mTORC1). TOR is a protein kinase that regulates cell size in many organisms throughout nature. mTORC1 inhibits catabolic processes including autophagy and activates anabolic processes including mRNA translation. mTORC1 regulation is achieved through two main upstream mechanisms. The first mechanism is regulation by growth factor signaling. The second mechanism is regulation by amino acids. Gene mutations that cause too much or too little mTORC1 activity lead to a spectrum of neuroanatomical changes ranging from altered brain size (micro and macrocephaly) to cortical malformations to Type I neoplasias. Because somatic mutations often underlie these changes, the timing, and location of mutation results in focal brain malformations. These mutations, therefore, provide gain-of-function and loss-of-function changes that are a powerful tool to assess the events that have gone awry during development and to determine their functional physiological consequences. Knowledge about the TSC-mTORC1 pathway has allowed scientists to predict which upstream and downstream mutations should cause commensurate neuroanatomical changes. Indeed, many of these predictions have now been clinically validated. A description of clinical imaging and histochemical findings is provided in relation to laboratory models of TSC that will allow the reader to appreciate how human pathology can provide an understanding of the fundamental mechanisms of development. [ABSTRACT FROM AUTHOR]

Objective: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease with many manifestations, and it involves any organ. In this study, we report a TSC patient with new type skin lesions.Methods: A 7-month-old TSC boy with multiple cutaneous nodules was admitted in our hospital. We collected the clinical data of the patient. We performed biopsy of cutaneous nodules and whole-exome sequencing in both paraffin block tissue and blood samples.Results: The patient presented with a 2 month history of gradual growth multiple cutaneous nodules. He had cardiac rhabdomyoma, subependymal giant cell astrocytoma (SEGA) and hypomelanotic macules. The pathological finding of cutaneous nodules was consistent with juvenile xanthogranuloma (JXG). After 3 months of sirolimus treatment, the multiple nodules disappeared. The whole-exome sequencing identified TSC1 (c.2356C > T, p.R786*) mutation in both paraffin block tissue and blood samples. We overturned the original pathological diagnosis and finally identified JXG as a new type of skin lesions in TSC.Conclusion: This is the first report on the occurrence of JXG skin lesions in TSC patient. Genetic testing is necessary in JXG. These findings expand the phenotype of skin in patients with TSC and contribute to the elucidation of JXG pathogenesis and treatment. [ABSTRACT FROM AUTHOR]

The following biopsy material yielded more tumor tissue which exhibited similar histomorphological features: the astrocytic tumor shows predominantly a solid growth pattern, regionally a mucoid matrix and appears to be relatively sharp demarcated from few smaller fragments of the adjacent CNS tissue. 6 Tumor cells and a GFAP-rich tumor matrix are visualized by immunohistochemical reaction against GFAP. In contrast, the present tumor displays mainly a solid growth pattern with monomorphic glial tumor cells. Tumors localized in the lateral ventricles of the cerebral hemispheres account for less than 1% of all intracranial tumors but are relatively more frequent in the pediatric population [[17]]. [Extracted from the article]

Background: Subependymal giant cell astrocytomas (SEGAs) appear approximately in 10% of patients with tuberous sclerosis. These tumors are most commonly diagnosed in childhood and adolescence, with in utero diagnosed SEGAs being an extremely rare entity. Case Description: We present the case of a congenital SEGA detected in an antenatal ultrasound and further investigated with fetal magnetic resonance imaging (MRI) scans at 22 and 32 weeks of gestational age. At 9 days of age, the child underwent craniotomy and partial excision of the tumor, followed by a second more extensive operation 13 days later. The patient was subsequently administered mammalian target of rapamycin inhibitor (everolimus). Conclusion: In the latest follow-up MRI, at the age of two, the SEGA remained unchanged. Management of these tumors in neonates is challenging, mainly due to high morbidity and mortality of surgical treatment in these ages. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a rare autosomal disorder that typically affects children. The manifestations of TSC include development of benign lesions in various organs, primarily in the brain, skin, kidneys, heart, and lungs. TSC management often involves multidisciplinary specialties. Herein, we present a case of a 5-year-old male patient who presented with a headache, vomiting and fever. Radiological assessment demonstrated a lobulated enhancing tumor in the right lateral ventricle near the foramen of Monro for which he underwent craniotomy (total tumor resection), which turned out to be subependymal giant cell astrocytomas upon histopathological examination. A follow-up MRI after 10 months showed cortical dysplasias, with tiny subependymal nodules. Dermatology examination revealed hypomelanotic macules, angiofibromas and shagreen patch. At his one-year follow-up, the patient exhibited normal mental and physical growth. Therefore, calling attention to TSC diagnosis and management depending upon the particular presentation may improve the quality of life of TSC patients.

Abstract Background Subependymal giant cell astrocytoma (SEGA) is a clinically benign brain tumor associated with tuberous sclerosis complex (TSC). There are still controversies on early diagnosis of the tumor. Methods CT and MR imaging of 20 patients with pathologically confirmed SEGA were retrospectively reviewed. Two radiologists evaluated the location, shape, size, number, edge, cerebral edema, homogeneous or heterogeneous appearance, attenuation and signal intensity, degree of enhancement and calcification of lesions. Their prognoses were based on clinical observations. Results SEGA showed similar features in imaging: an extra-axial, well-circumscribed, periventricular mass, isodense or slightly hyperdense on CT, hypointensity on T1-weighted imaging and isointensity to hyperintensity on T2-weighted imaging. The mass enhanced markedly and heterogeneously after the administration of contrast agent. Subependymal nodules were demonstrated in 5 cases. Remarkably, 17 patients (85%) showed ventricular dilatation and 14 patients (70%) showed calcification in CT and MR imaging. Moreover, perifocal edema was not significantly near the masses. Four cases are associated with tuberous sclerosis complex (TSC). Conclusions Although there are no pathognomonic imaging findings for SEGA, the following clinical and imaging features might be helpful for the diagnosis, such as the initial age of first or second decade, typical location in the periventricular regions adjacent to the foramen of Monro, hydrocephalus accompanied with raised intracranial pressure, TSC and marked heterogeneous enhancement.

Objective: Everolimus is the only FDA approved drug to treat renal angiomyolipoma or subependymal giant-cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC). Potential differences exist between patients with commercial and Medicaid insurance on everolimus use; however, there is limited information from the real world. This study compared compliance and persistence of everolimus between commercial and Medicaid patients using US claims data.Methods: Patients with ≥1 claim of TSC with renal angiomyolipoma or SEGA were selected from the MarketScan commercial (1 January 2009-31 August 2016) and Medicaid (1 January 2009-30 June 2015) databases. Patients were followed from index date (the earliest date of TSC, renal angiomyolipoma or SEGA diagnosis) to death or end of data. Non-persistence, defined as ≥60 day gap without everolimus, and medication possession ratio (MPR) were assessed among the subset of patients with ≥1 year of follow-up from the first everolimus claim.Results: A total of 1497 TSC patients met the study criteria (896 renal angiomyolipoma only, 411 SEGA only and 190 both). Compared to Medicaid patients (N = 513), commercial patients (N = 984) had the same ages (22 years) but a shorter length of follow-up (38 vs. 48 months, p < .001). Medicaid and commercial patients had similar rates of being treated with everolimus (14.4% vs. 13.6%, p = .668), but it took Medicaid patients a longer time to start everolimus (871 vs. 704 days, p < .001). Although the non-persistence rate was not significantly different between commercial and Medicaid patients (42.5% vs. 35.1%, p = .561), the number of days from everolimus initiation to non-persistence was significantly lower for commercial patients (945 vs. 1132, p < .001). During the 1 year post everolimus initiation, commercial patients had a significantly higher MPR (0.81 vs. 0.74, p < .001) and higher percentage of patients with MPR ≥0.80 (67.8% vs. 58.1%, p < .001).Conclusions: Among TSC patients with renal angiomyolipoma or SEGA and treated with everolimus, everolimus MPR was between 0.74 and 0.81. Medicaid patients had lower MPR than commercial patients but better persistence. [ABSTRACT FROM AUTHOR]

Subependymal giant cell astrocytoma (SEGA) is a low grade (WHO Grade I) tumor, usually seen in patients with tuberous sclerosis complex and commonly occurs at a lateral ventricular location. Intraoperative squash cytologic features can help in differentiating SEGA from gemistocytic astrocytoma (GA), giant cell glioblastoma and ependymoma, in proper clinical context and radiological findings, which may alter the surgical management. Here, we present a case of SEGA with squash cytologic findings and a review of cytology findings of SEGA presently available in the literature. Loose cohesive clusters of large polygonal cells containing an eccentric nucleus, evenly distributed granular chromatin, distinct to prominent nucleoli, and moderate to the abundant eosinophilic cytoplasm in a hair-like fibrillar background are the key cytologic features of SEGA. Other important features are moderate anisonucleosis and frequent binucleation and multinucleation. The absence of mitoses, necrosis, and vascular endothelial proliferation are important negative features. Other consistent features are cellular smears, few dispersed cells, few spindly strap-like cells, rare intranuclear cytoplasmic inclusion, and perivascular pseudorosettes.

• Tuberous sclerosis complex (TSC) is caused by TSC1/TSC2 gene mutations. • Subependymal giant cell astrocytomas (SEGAs) are rare tumours seen in TSC. • Solitary SEGAs without detectable mutation or other TSC manifestations are rare. Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant hamartoma syndrome caused by mutations in TSC1 or TSC2 genes, leading to upregulation of cell growth signalling pathways. Subependymal giant cell astrocytomas (SEGAs) are seen almost exclusively in TSC patients. We report a 'solitary SEGA' in an adult patient, with confirmed deletion of the entire TSC2 gene on tumour tissue DNA, in the absence of detectable constitutional mutation or clinical manifestations of TSC. These rare cases may be secondary to somatic mosaicism and provide an opportunity to explore the genetic basis of the syndrome and its related tumours. [ABSTRACT FROM AUTHOR]

Objective: Subependymal giant cell astrocytomas (SEGAs) are WHO grade 1 tumors associated with tuberous sclerosis that classically arise from the ventricular wall near the caudate groove and foramen of Monro. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique, which works by heating a stereotactically placed laser fiber to ablative temperatures under MRI thermometry monitoring. In this paper, the authors present LITT as a surgical alternative to open resection of SEGAs., Methods: Twelve patients with SEGAs who underwent 16 procedures between 2007 and 2022 at a single institution were retrospectively reviewed. These patients underwent either open resection or LITT. Clinical data, imaging, recurrence rate, further treatments, and related complications were analyzed., Results: Among the 16 procedures, 9 were open resection and 7 were LITT. An external ventricular drain was placed in 66% (6/9) of open procedures and 57.1% (4/7) of LITT cases. A septostomy was performed in 56% (5/9) of open procedures and 29% (2/7) of LITT cases. Complication rates were higher in open cases than in LITT procedures (44% vs 0%, p < 0.05). Complications included hydrocephalus, transient venous ischemia, wound infection, and bone flap migration. The median length of hospital stay was 4 days (IQR 3.3-5.5 days) for open cases and 4 days (IQR 3.0-7.0 days) for LITT procedures. Recurrence or progression occurred after 3 open cases and 2 LITT cases (33% vs 33%, p = 0.803). For the recurrences, 2 open cases underwent stereotactic radiosurgery, 1 open case underwent LITT, and 1 LITT case underwent repeat LITT. Among the LITT cases, only the patients with no decrease in tumor size by 6 months experienced tumor progression afterward. The 2 LITT cases with progression were the only ones with calcification present on preoperative imaging. The median follow-up times for cases assessed for progression were 8.4 years (IQR 3.8-14.4 years) for open resection and 3.9 years (IQR 3.4-5.1 years) for LITT., Conclusions: The small size of this case series limits generalizability or adequate comparison of safety. However, this series adds to the literature supporting LITT as a less invasive surgical alternative to open resection of SEGAs and demonstrates that LITT has similar recurrence and/or progression rates to open resection. Additional studies with more data are necessary for comprehensive comparisons between open resection and LITT for treating SEGA.

Background Subependymal giant cell astrocytoma (SEGA) is a rare, benign neoplasm predominantly associated with tuberous sclerosis complex. Clinical outcomes have largely been conveyed via small- and medium-sized case series. Methods With the Surveillance, Epidemiology, and End Results Program (SEER)–18 registry database, information from all patients diagnosed with SEGA from 2004 to 2013 was obtained (age, sex, race, marital status, tumor size, tumor location, occurrence of surgery, receipt of radiation, and follow-up data). Age-adjusted incidence rates and overall survival (OS) were determined. Cox proportional hazards model was used for both univariate and multivariate analyses. Results The overall incidence of SEGA within the SEER-18 database is 0.027 per 100,000 person-years (95% confidence interval, 0.024–0.031). A total of 226 cases were identified. For OS, univariate analysis revealed age younger than 18 years (hazard ratio [HR], 0.214; P = 0.004) and occurrence of surgery (HR, 0.328; P = 0.039) were significant positive prognostic factors. Sex, marital status, race, tumor size, tumor location, and receipt of radiation did not exhibit significant relationships. Interestingly, subanalysis for extent of resection to gross total resection did not show benefit. Multivariate analysis revealed that both age younger than 18 years (HR, 0.193; P = 0.002) and occurrence of surgery (HR, 0.286; P = 0.021) remained significant. Conclusions Based on our analysis, younger age and occurrence of surgery are significant independent factors associated with better OS. There was no support for radiation. Highlights • SEGA is a rare, benign neoplasm predominantly associated with TSC. • Clinical outcomes have largely been conveyed via small- and medium-sized case series. • Younger age and occurrence of surgery are significant independent factors associated with better OS. • There was no support for radiation. • Subanalysis for extent of resection to GTR did not show benefit. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder that activates mammalian target of rapamycin and produces tumor growth in several organs. We present five patients younger than 12 months who were diagnosed with TSC and treated with everolimus (EVL), after which congenital subependymal giant astrocytoma (cSEGA) promptly regressed in all patients. All patients achieved at least 50% reduction in the volume of cSEGA within 6 months. The most rapid reduction of cSEGA volume (79.1%) was found during the initial 3 months of EVL treatment. Patients underwent EVL treatment for an average of 27 months (range: 4–55 months). Mean EVL maintenance dose was 1.35 mg per day. EVL blood trough concentrations ranged from 2.0 to 11.7 ng/ml. The cSEGA became larger after discontinuing EVL in two patients. In all four patients who had multiple cardiac rhabdomyomas (CRMs), the CRMs showed accelerated regression after receiving EVL. Adverse events were noted in four patients: infection, stomatitis, and increased triglycerides. Four patients had febrile status epilepticus, which occurred during acute encephalopathy in a patient, and after discontinuing EVL in another. Three patients were still receiving EVL at their latest evaluations. Maintenance therapy with EVL is an effective therapeutic option for patients with cSEGA, and moreover may have additional favorable effects on other complications, even in early infancy; however, adverse effects should be carefully monitored. [ABSTRACT FROM AUTHOR]

Background Tuberous sclerosis complex (TSC) is a rare genetic disorder with multisystem involvement. A magnetic-resonance (MRI) based classification of tubers into types A, B and C has been proposed. However, the relationship between different tuber types and their quantitative characteristics, also the non-neurological manifestations of TSC remains unknown. Aims To quantitatively evaluate different MRI-defined tuber types and to explore their relationships with major disease manifestations in patients with tuberous sclerosis complex. Methods We performed quantitative manual assessment of tubers visible on T1W, T2W/FLAIR images and DW/ADC maps of 20 patients with TSC. Tubers were classified into types A, B and C based on their signal intensity on MRI. General clinical information and quantitative tuber characteristics were evaluated. Between-group comparisons were made using the nonparametric Mann-Whitney U test with Bonferroni correction. Results In total, 20 patients with 770 tubers were evaluated. Type A tubers were most numerous followed closely by Type B tubers, whereas Type C tubers were relatively rare. Tuber size was markedly different among the three tuber types: it increased from Type A to Type B to Type C. Infantile spasms, generalized-tonic clonic seizures, poor seizure control, cardiac rhabdomyomas, SEGA and developmental delay were not associated with quantitative tuber characteristics. Increased total Type B tuber load was associated with early onset epilepsy, while individually larger Type A and Type B tubers were associated with the presence angiomyolipoma (AML) and renal cysts. Conclusions MRI-defined tuber types differ significantly in their size and number. Larger total Type B tuber load and larger individual Type A and Type B tubers were found to be most associated with early seizure onset and renal angiomyolipomas, respectively. One possible explanation for the observed differences in the clinical phenotype based on MRI-defined tuber types is not the intrinsic qualitative distinctions between different tuber types, but rather their individual size and total tuber load. [ABSTRACT FROM AUTHOR]

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/m/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. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystemic disorder caused by deregulation of the mTOR pathway, and represents one of the leading genetic causes of epilepsy. mTOR inhibitors (Sirolimus and Everolimus) are currently approved only for the treatment of growing subependymal giant cell astrocytomas, renal angiomyolipomas and lymphangioleiomyomatosis in TSC. However, preclinical and clinical evidence supports their potential role in effectively treating TSC-associated epilepsy, but no consensus on its use in seizures has been reached yet and there are few data on epilepsy outcome after the suspension of mTOR inhibitors treatment. We report for the first time on a patient in whom discontinuation of Everolimus (prescribed for growing subependymal giant cell astrocytomas) was associated with a relapse of seizures twice, and control of seizures was regained after reintroducing the medicine. This clinical report supports the promising potential of Everolimus in treating epilepsy in TSC, and specifically underlines the non-permanent effect on seizures after withdrawal. [ABSTRACT FROM AUTHOR]

Introduction: Tuberous sclerosis is associated with three central nervous system pathologies: cortical/subcortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Tubers are associated with epilepsy, which is often medication-resistant and often leads to resective surgery. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be effective reducing seizure burden in some patients with tuberous sclerosis complex (TSC)-related refractory epilepsy. mTORi have also been shown to be an alternative for surgery treating SEGAs. We describe several cases of resected tubers that contained SEGA tissue without an intraventricular SEGA. Methods: After institutional review board (IRB) protocol approval, we retrospectively reviewed the surgical-pathological data for all TSC patients who underwent cortical resections for treatment of refractory epilepsy at NYU Langone Medical Center and Tel Aviv Medical Center between 2003 and 2013. Data included demographics, epilepsy type, MRI characteristics, epilepsy outcome, and histopathological staining. Results: We reviewed cortical resections from 75 patients with complete pathological studies. In three patients, cortical lesions demonstrated histopathological findings consistent with a SEGA within the resected tuber tissue, with no intraventricular SEGA. All lesions were cortically based and none had any intraventricular extension. No patient had been treated before surgery with an mTORi. Two of the three patients remain Engel grade I-II. All lesions stained positive for glial fibrillary acidic protein (GFAP), synaptophysin, and neuronal nuclear antigen (NeuN). Conclusion: This is the first description of cortical tubers harboring SEGA tissue. This observation though preliminary may suggest a subgroup of patients with intractable epilepsy in whom mTORi may be considered before surgical intervention. [ABSTRACT FROM AUTHOR]

Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Many gaps remain in the understanding of TSC because of the complexity in clinical presentation. The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to address knowledge gaps in the natural history and management of TSC. Here, we present the baseline data of TOSCA cohort.Methods: Patients of any age diagnosed with TSC, having a documented visit for TSC within the preceding 12 months, or newly diagnosed individuals were included. The registry includes a "core" section designed to record detailed background information on each patient including disease manifestations, interventions, and outcomes collected at baseline and updated annually. "Subsections" of the registry recorded additional data related to specific features of TSC.Results: Baseline "core" data from 2093 patients enrolled from 170 sites across 31 countries were available at the cut-off date September 30, 2014. Median age of patients at enrollment was 13 years (range, 0-71) and at diagnosis of TSC was 1 year (range, 0-69). The occurrence rates of major manifestations of TSC included - cortical tubers (82.2%), subependymal nodules (78.2%), subependymal giant cell astrocytomas (24.4%), renal angiomyolipomas (47.2%), lymphangioleiomyomatosis (6.9%), cardiac rhabdomyomas (34.3%), facial angiofibromas (57.3%), forehead plaque (14.1%), ≥ 3 hypomelanotic macules (66.8%), and shagreen patches (27.4%). Epilepsy was reported in 1748 (83.5%) patients, of which 1372 were diagnosed at ≤ 2 years (78%). Intellectual disability was identified in 451 (54.9%) patients of those assessed. TSC-associated neuropsychiatric disorders (TAND) were diagnosed late, and not evaluated in 30-50% of patients.Conclusion: TOSCA is the largest clinical case series of TSC to date. It provided a detailed description of the disease trajectory with increased awareness of various TSC manifestations. The rates of different features of TSC reported here reflect the age range and referral patterns of clinics contributing patients to the cohort. Documentation of TAND and LAM was poor. A widespread adoption of the international TSC assessment and treatment guidelines, including use of the TAND Checklist, could improve surveillance. The registry provides valuable insights into the necessity for monitoring, timing, and indications for the treatment of TSC. [ABSTRACT FROM AUTHOR]