Giant Cell Astrocytoma Research Articles

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile.

Subependymal giant-cell astrocytomas (SEGAs) are slow-growing brain tumors that are a hallmark feature seen in 5-10% of patients with Tuberous Sclerosis Complex (TSC). Though histologically benign, they can cause serious neurologic symptoms, leading to death if untreated. SEGAs consistently show biallelic loss of TSC1 or TSC2. Herein, we aimed to define other somatic events beyond TSC1/TSC2 loss and identify potential transcriptional drivers that contribute to SEGA formation. Paired tumor-normal whole-exome sequencing was performed on 21 resected SEGAs from 20 TSC patients. Pathogenic variants in TSC1/TSC2 were identified in 19/21 (90%) SEGAs. Copy neutral loss of heterozygosity (size range: 2.2-46 Mb) was seen in 76% (16/21) of SEGAs (44% chr9q and 56% chr16p). An average of 1.4 other somatic variants (range 0-7) per tumor were identified, unlikely of pathogenic significance. Whole transcriptome RNA-sequencing analyses revealed 190 common differentially expressed genes in SEGA (n = 16, 13 from a prior study) in pairwise comparison to each of: low grade diffuse gliomas (n = 530) and glioblastoma (n = 171) from The Cancer Genome Atlas (TCGA) consortium, ganglioglioma (n = 10), TSC cortical tubers (n = 15), and multiple normal tissues. Among these, homeobox transcription factors (TFs) HMX3, HMX2, VAX1, SIX3; and TFsIRF6 and EOMES were all expressed >12-fold higher in SEGAs (FDR/q-value < 0.05). Immunohistochemistry supported the specificity of IRF6, VAX1, SIX3 for SEGAs in comparison to other tumor entities and normal brain. We conclude that SEGAs have an extremely low somatic mutation rate, suggesting that TSC1/TSC2 loss is sufficient to drive tumor growth. The unique and highly expressed SEGA-specific TFs likely reflect the neuroepithelial cell of origin, and may also contribute to the transcriptional and epigenetic state that enables SEGA growth following two-hit loss of TSC1 or TSC2 and mTORC1 activation.

The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma

Background: Facial angiofibromas may be present since early childhood in individuals with tuberous sclerosis complex (TSC), causing substantial cosmetic disfigurement. Current therapies are partially effective, but they are uncomfortable, produce scarring, and are especially expensive. Objective: The aim of the present study was to evaluate the efficacy of oral everolimus for TSC-associated angiofibromas. Methods: This retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibromas. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus. Results: Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11–44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004). Conclusion: Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The current study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC.

Current trends in the management of subependymal giant cell astrocytomas in tuberous sclerosis.

The management of subependymal giant cells astrocytomas (SEGAs) has been traditionally represented by surgical treatment through an open craniotomic approach. Though open surgery still represents a major option in the management of this kind of tumors, the introduction of mTOR inhibitors in the clinical practice, technological advances in neuroendoscopy and the more recent use of laser interstitial therapy have significantly enlarged the range of available management opportunities. A thorough review of the literature has been performed. Accordingly, current views in open surgical treatment, medical therapy, endoscopic tumor removal and new trends (such as laser interstitial thermal therapy) are discussed. The risk of significant neurological morbidity (5-50%) complicating open surgery has been for a long time representing a main drawback in the management of SEGAs. More recent series report a significant reduction of morbidity and mortality. The mTOR inhibitors have demonstrated efficacy in both warranting a tumor reduction by up to 60% of the tumor size and helping the control of seizures. However, the reported rate of side effects is as high as 30% and tumor recurrence is a documented occurrence at the time of mTOR inhibitor discontinuation. Endoscopic tumor removal has been more extensively considered an option due to the acquisition of new tools. Limits are still represented by tumor size (< 3 cm) and broad attachment of the tumor to the basal ganglia. Laser interstitial thermal therapy (LITT)is the more recently considered option. Though promising, only short follow-up is available so far, while data on medium- and long-term results of this treatment are completely lacking to date. Surgical treatment remains a mainstay of the management of SEGAs. The indication for an open craniotomic approach should be balanced with an endoscopic tumor removal or LITT according to patient conditions, presence or not of an active hydrocephalus and extension of the attachment of the tumor to the basal ganglia. The mTOR inhibitors do have a definite role both as primary and as adjuvant treatment, but consistent limitations are represented up to now by a not negligible rate of complications and the uncertainties related to the possibility of tumor recurrence once the medical treatment is discontinued.

TSC2 pathogenic variants are predictive of severe clinical manifestations in TSC infants: results of the EPISTOP study

To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

WT1 Clone 6F-H2 Cytoplasmic Expression Differentiates Astrocytic Tumors from Astrogliosis and Associates with Tumor Grade, Histopathology, IDH1 Status, Apoptotic and Proliferative Indices: A Tissue Microarray Study.

Objectives:This tissue microarray (TMA) immunohistochemical (IHC) study elucidates the role of Wilms’ tumor 1 protein (WT1) in diagnosis and prognostication of astrocytic tumors. Methods:IHC was applied to 75 astrocytic lesions (18 astrogliosis and 57 astrocytic tumors) using antibodies directed against WT1 clone 6F-H2, isocitrate dehydrogenase 1(IDH1), Bcl2 and Ki67. WT1 IHC staining was evaluated and scored blindly by 2 pathologists. Bcl2 and Ki67 scores and labelling indices were assessed and IDH1 status determined. Statistical analysis was performed using the appropriate methodology. Results:WT1 cytoplasmic expression was detected in 89.5% of astrocytic tumors but not in astrogliosis. Positive WT1 differentiated astrocytic tumors (92.6% accuracy) and grade II diffuse astrocytomas (93.5% accuracy) from astrogliosis with high sensitivity, specificity and positive predictive values (p<0.001). Increased WT1 score significantly associated higher Bcl2 and Ki67 labelling indices, increasing WHO tumor grade and tumor’s histopathologic type (p<0.05) showing staining pattern variability by tumor entity and cell type. Glioblastomas, gliosarcomas and subependymal giant cell astrocytomas were the most frequently WT1 expressing tumors with frequent +3 WT1 score. About 21.4% of pilocytic astrocytomas had +3WT1 score in association with increased Bcl2 and Ki67 indices. Low WT1 scores in grade II and III diffuse astrocytomas were linked to the high frequency of IDH1 positivity, and were associated with low Bcl2 and Ki67 labelling indices. In glioblastomas, WT1 significantly associated poor prognostic variables: older age, negative-IDH1 status, high Bcl2 and Ki67 labelling indices (p=0.04, <0.001, =0.001 and <0.001 respectively). Conclusions:WT1 clone 6F-H2 is a highly accurate positive surrogate marker to differentiate astrocytic tumors notably the challenging grade II diffuse astrocytoma from astrogliosis. It significantly associates with poor prognostic variables including IDH1 negativity, high apoptotic and proliferative indices and depends on tumor’s histopathologic entity more than its grade. Evaluation of WT1 expression seems essential to tailor patient’s therapy.

A Patient with Tuberous Sclerosis Complex and Spinal Muscular Atrophy; A Case Report

Background Tuberous Sclerosis Complex (TSC), and Spinal Muscular Atrophy (SMA) are two inherited disorders while they are genetically independent. TSC is characterized by the formation of multiple hamartomas in nearly all organs. SMA is a destructive neurological disorder leading to progressive muscular weakness and atrophy. Case Presentation The patient was an Iranian (Urmia, East Azerbaijan Province, Iran) 11-year-old daughter of non-consanguineous parents. She developed seizures as an infantile spasm at three months old. She had a delay in motor development. At 11 years old, the patient had proximal muscle weakness resulting in a characteristic waddling gait and Gowers’ sign, which was suspected of SMA. The SMA was then confirmed using molecular analysis. Clinical examination of the patient revealed angiofibromas, shagreen patch, and hypopigmented spots on the skin; cortical tubers, subependymal nodules, and subependymal giant cell astrocytoma in the brain; angiomyolipomas in the kidneys; and retinal hamartoma, which fulfilled the diagnostic criteria of TSC. Conclusion Although TSC and SMA are genetically independent disorders, they may rarely occur together in an individual, simultaneously. Further studies required to find the patterns of genetic inheritance of these diseases among the reported patient.

Subependymal Giant Cell Astrocytoma without Clinically or Genetically Identifiable Tuberous Sclerosis Complex: A Case Report

Background: Subependymal giant cell astrocytoma (SEGA) is a World Health Organization grade I tumor most commonly located in the lateral ventricles near the foramen of Monro. They are primarily associated with tuberous sclerosis complex (TSC), an autosomal dominant inherited condition that leads to a variety of tumors throughout the body. TSC must be diagnosed via either genetic criteria or clinical criteria. Cases of SEGA in patients without both genetically or clinically identifiable TSC are scarce, with only two instances identified of those genetically screened in the literature. We describe what we believe is only the third such case, a 22-year-old patient with no other clinical or genetic indicators for tuberous sclerosis. Case Description: The patient is a 22-year-old Caucasian female who experienced progressive symptoms of headaches, tinnitus and visual obscuration. A magnetic resonance imaging study of the brain revealed a homogeneously enhancing mass in the right lateral ventricle with obstruction of the foramen of Monro. The patient underwent a right frontal craniotomy for transcortical-transventricular resection of the mass. Histologic examination of the tumor revealed a diagnosis of SEGA. Germline genetic tests for both TSC1 and TSC2 were negative, and no additional clinical features were present. The patient was thus not felt to meet the criteria for a diagnosis of TSC based on the absence of clinical features, family history, and negative genetic testing. Conclusion: Although a rare phenomenon, SEGA should remain on the differential diagnosis for patients with newly found periventricular tumors and absence of TSC clinical features.

Recombinant Tissue Plasminogen Activator Use in an Acute Stroke Patient With Tuberous Sclerosis

Tuberous sclerosis (TS) is an autosomal dominant disease known for over a century and recognized by characteristic hamartomatous lesions involving any organ. In this report, we are presenting a patient with TS who presented with acute embolic stroke and received tissue plasminogen activator (tPA) and had a mechanical thrombectomy (MT). She had a dramatic response without any hemorrhagic complications. She is a 68-year-old Caucasian woman with the past medical history of TS since childhood who presented to the hospital with symptoms of left middle cerebral artery (MCA) syndrome (right-sided weakness, sensory loss, right facial droop, aphasia, hemianopia, and dysarthria). National Institute of Health Stroke Scale (NIHSS) score was 19. Head computed tomography (CT) was negative for any acute abnormality except cortical tubers, subependymal ventricular calcification. CT angiography of the head and neck showed proximal occlusion of the left internal carotid artery. After ruling out all exclusion criteria, the patient received tPA and had an MT with complete reperfusion (thrombolysis in cerebral infarction (TICI) 3). Brain magnetic resonance imaging (MRI) showed an acute stroke in the multivessel territories (bilateral parietal cortices, the left lentiform nucleus, medial left temporal lobe, left thalamus, and right occipital lobe) suggestive of an embolic phenomenon and did not show any hemorrhagic complication. TS patients are at increased risk of intracerebral hemorrhage either in the setting of vascular malformation or due to hemorrhage into the subependymal giant cell astrocytoma. The best explanation for the latter could be secondary to elevated venous pressure from increased intracranial pressure. Fortunately, our TS patient who presented with acute ischemic stroke was within the window and received tPA and MT. The patient not only did not have any hemorrhagic side effects afterward but also had a significant improvement in her neurologic symptoms. To our best knowledge, this is the only case report of tPA administration in a TS patient. Moreover, we need more case reports to evaluate the safety of tPA in these patients. J Neurol Res. 2020;10(4):140-143 doi: https://doi.org/10.14740/jnr595

Juvenile xanthogranuloma as a new type of skin lesions in tuberous sclerosis complex

ObjectiveTuberous 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.MethodsA 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.ResultsThe 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.ConclusionThis 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.

Congenital subpendymal giant cell astrocytoma in children with tuberous sclerosis complex: growth patterns and neurological outcome.

Literature regarding congenital subependymal giant cell astrocytomas (SEGA) is limited, and suggests they are at risk of rapid growth and complications. We sought to characterise the growth patterns of congenital SEGA. The second part of the study was an exploratory analysis of congenital SEGA as a possible biomarker for poor neurological outcome. This single-centre case series describes ten patients with TSC who had SEGA diagnosed before 12 months. SEGA diameter and volumetric growth were analysed using serial MRIs. Neurological outcomes were compared to a genotype-matched group. All children with congenital SEGA had a TSC2 mutation. Patients were followed for 1-8.7 years, during which median SEGA growth rate was 1.1 mm/yr in diameter or 150 mm3/yr volumetrically. SEGA with volume > 500 mm3 had a significantly higher growth rate compared with smaller SEGA (462 mm3/yr vs. 42 mm3/yr, p = 0.0095). Children with congenital SEGA had a high prevalence of severe epilepsy, developmental disability and autism spectrum disorder. Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Frequent neuroimaging surveillance is recommended for congenital SEGA with volumes exceeding 500 mm3. Congenital SEGA occur in 9.2% of paediatric patients with tuberous sclerosis complex. There are few published cases of congenital SEGA to date. This case series of ten patients adds our experience seen in a tertiary referral hospital over 10 years. Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Congenital SEGA with volume exceeding 500 mm3 had a significantly higher growth rate compared with smaller SEGA and should have more frequent neuroimaging surveillance.

Dysregulation of the MMP/TIMP Proteolytic System in Subependymal Giant Cell Astrocytomas in Patients With Tuberous Sclerosis Complex: Modulation of MMP by MicroRNA-320d In Vitro.

Tuberous sclerosis complex (TSC), a rare genetic disorder caused by a mutation in the TSC1 or TSC2 gene, is characterized by the growth of hamartomas in several organs. This includes the growth of low-grade brain tumors, known as subependymal giant cell astrocytomas (SEGA). Previous studies have shown differential expression of genes related to the extracellular matrix in SEGA. Matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) are responsible for remodeling the extracellular matrix and are associated with tumorigenesis. This study aimed to investigate the MMP/TIMP proteolytic system in SEGA and the regulation of MMPs by microRNAs, which are important post-transcriptional regulators of gene expression. We investigated the expression of MMPs and TIMPs using previously produced RNA-Sequencing data, real-time quantitative PCR and immunohistochemistry in TSC-SEGA samples and controls. We found altered expression of several MMPs and TIMPs in SEGA compared to controls. We identified the lowly expressed miR-320d in SEGA as a potential regulator of MMPs, which can decrease MMP2 expression in human fetal astrocyte cultures. This study provides evidence of a dysregulated MMP/TIMP proteolytic system in SEGA of which MMP2 could be rescued by microRNA-320d. Therefore, further elucidating microRNA-mediated MMP regulation may provide insights into SEGA pathogenesis and identify novel therapeutic targets.

Stereotactic laser ablation for subependymal giant cell astrocytomas: personal experience and review of the literature.

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. 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 2.5min, with post-ablation scans for visualization of treatment area. Average age at surgery was 8.2years. Pre-operative tumor volumes were 0.43, 1.51, and 3.88cm3. Post-operative tumor volumes were 0.25, 0.21, and 0.68cm3. Mean tumor volume reduction was 70%. No complications occurred. LITT with septostomy should be considered a viable primary or adjunct treatment modality for SEGAs.

Subependymal giant cell astrocytoma associated with hyperproteinorrhachia, presented with vp shunt malfunction: a rare clinical entity

Subependymal giant cell astrocytomas (SEGAs) are WHO grade I tumors, most frequently associated with tuberous sclerosis complex (TSC). TSC sometimes also called Bourneville’s disease is a neurocutaneous disorder characterized by hamartoma of many organs like skin, brain, eye and kidneys. In this report, we illustrate the case of SEGA with hydrocephalus, who presented with features of raised intracranial pressure, along with shunt malfunction due to shunt valve blockage with proteinaceous material. Patient underwent interhemispheric transcallosal approach and complete removal of tumor followed by ventriculo- atrial shunt and achieved favourable outcome.

Tuberous Sclerosis–Associated Renal Neoplasm

A man in his thirties presented with bilateral renal masses and well-controlled hypertension. He had a history of resection of a brain lesion in early childhood. Imaging studies did not reveal cystic lung disease. Bilateral nephrectomies were performed because of end-stage renal disease, and both kidneys were replaced by fibrotic and lobulated masses. Histopathological examination revealed extensive involvement by angiomyolipoma bilaterally. What syndrome should this patient be screened for, and what are some other common associated features?a.Birt-Hogg-Dubé syndrome: benign tumors of the skin and spontaneous pneumothorax secondary to cystic lung diseaseb.von Hippel-Lindau disease: central nervous system hemangioblastomas and pheochromocytomasc.Li-Fraumeni syndrome: osteosarcoma, adrenocortical carcinoma, and central nervous system tumorsd.Tuberous sclerosis complex: subependymal giant cell astrocytomas, cardiac rhabdomyomas, and lymphangioleiomyomatosis Answer: d. Tuberous sclerosis complex: subependymal giant cell astrocytomas, cardiac rhabdomyomas, and lymphangioleiomyomatosis Tuberous sclerosis complex is associated with renal manifestations including renal angiomyolipomas and a wide spectrum of renal neoplasia that have variable morphological features.1Guo J. Tretiakova M.S. Troxell M.L. et al.Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients.Am J Surg Pathol. 2014; 38: 1457-1467Crossref PubMed Scopus (129) Google Scholar Two major diagnostic features or a combination of 1 major and at least 2 minor diagnostic features are required to establish a clinical diagnosis.2Henske E.P. Jóźwiak S. Kingswood J.C. Sampson J.R. Thiele E.A. Tuberous sclerosis complex.Nat Rev Dis Primers. 2016; 2: 16035Crossref PubMed Scopus (214) Google Scholar Major diagnostic criteria for tuberous sclerosis include hypomelanotic macules (≥3 of ≥5 mm in diameter), angiofibromas (≥3) or fibrous cephalic plaques, ungual fibromas (≥2), shagreen patches, multiple retinal hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytomas, cardiac rhabdomyomas, lymphangioleiomyomatosis, and angiomyolipomas (≥2). Tuberous sclerosis complex is an autosomal dominant disorder associated with loss-of-function alterations in TSC1 and TSC2 genes (for expansion of gene symbols, use search tool at www.genenames.org). von Hippel-Lindau disease, secondary to germline alterations in the VHL gene, is associated with clear cell renal cell carcinoma, central nervous system hemangioblastoma, and pheochromocytoma. Li-Fraumeni syndrome, secondary to germline alterations in the TP53 gene, is associated with osteosarcoma, adrenocortical carcinoma, and central nervous system tumors. Finally, Birt-Hogg-Dubé syndrome, secondary to germline alterations in the FLCN gene, is associated with hybrid renal tumors, benign tumors of the skin, and spontaneous pneumothorax secondary to cystic lung disease.

Problems of differential diagnosis of focal brain lesions in patients with HIV infection

Currently, the leading cause of social disadaptations and disability of patients at advanced stages of HIV infection, as well as adverse outcomes, is the presence of severe comorbid variants of the course of HIV infection: HIV and co-infection of chronic viral hepatitis, tuberculosis, HIV and malignant tumors, and HIV-associated neurological diseases. In pediatric practice, the combination of HIV-induced and perinatal CNS lesions is the most relevant. The differential diagnosis of these conditions is complicated due to the polymorphism of clinical manifestations and the possibility of combining several pathological conditions simultaneously in patients. Neuroimaging data does not always have clear criteria for determining the exact cause of cerebral damage. The article presents data of own clinical neuroimaging observations of two patients with perinatal and parenteral HIV infection. The nervous system damage was polyetiological in nature and was presented in one case by a combination of HIV-encephalitis, cerebral toxoplasmosis and CNS lymphoma, in the second by the presence of Bourneville-Pringle disease (tuberous sclerosis) with the formation of giant-cell astrocytoma and HIV-induced brain damage. It should be noted that the optimization of the antiretroviral therapy regimen in the case of a combination of B-cell lymphoma and cerebral toxoplasmosis in a child with perinatal HIV infection led to clinical and laboratory remission

A retrospective analysis of the efficacy and tolerability of treatment with everolimus in treatment-refractory epilepsy associated with tuberous sclerosis

Rationale: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by multiple multi-organ hamartomas. Medically refractory epilepsy (MRE) occurs in up to 60% of TSC patients. The results of the EXIST-3 study have shown the efficacy of MRE treatment with an mTOR inhibitor everolimus. In the Russian Federation, the drug has been approved since 2017 for the treatment of TSC-associated MRE in patients above 2 years of age. Aim: To assess the efficacy of everolimus for treatment of medically refractory seizures associated with TSC. Materials and methods: We retrospectively analyzed medical files from 89 patients with TSC who had been admitted with MRE to the Department of Psychoneurology and Epileptology, Research and Clinical Institute for Pediatrics (Moscow, Russia) from November 2016 to December 2018. The patients were divided into three groups depending on their indications for everolimus: 1) 17 patients received with MRE; 2) 64 patients with MRE and subependymal giant cell astrocytoma (SEGA) of &gt; 1 cm in diameter; 3) 8 patients with MRE and renal angiomyolipoma (AML) of &gt; 3 cm in diameter. Their median age was 7.9 year (range, from 2 to 34 years). There were 45 (50.6%) male and 44 (49.4%) female patients. Their treatment lasted from 6 months to 5 years; the dose of everolimus was 8 mg/m2 . Focal seizures were more prevalent than epileptic spasms: 60 (67.4%) and 29 (32.6%) patients, respectively. Results: There were 9/17 (52.9%) responders in the MRE group, 16/64 (25%) in the MRE + SEGA group, and 4/8 (50%) in the MRE + AML group. Mild to moderate stomatitis was the most frequent side effect (40.5%). Conclusion: Everolimus is a new important agent for MRE in TSC patients. Treatment with everolimus is safe and well tolerated.

Prédisposition héréditaire aux tumeurs des systèmes nerveux central et périphérique

Some tumors of the central and peripheral nervous system may be associated with a cancer predisposition syndrome, either hereditary or occurring de novo. Such a syndrome is usually associated with multiple tumors occurring early in life. Patients with neurofibromatosis type 1 present with multiple neurofibromas, especially of the plexiform type (which may transform into malignant peripheral nerve sheath tumor), and pilocytic astrocytomas of the optic pathways. Neurofibromatosis type 2 patients present with multiple schwannomas (typically bilateral vestibular schwannomas), meningiomas, and ependymomas. Li-Fraumeni syndrome (germline TP53 mutation) is associated with choroid plexus tumors (carcinomas), medulloblastomas, and diffuse astrocytomas. Multiple hemangioblastomas are characteristic of von Hippel-Lindau syndrome while subependymal giant cell astrocytomas are pathognomonic of tuberous sclerosis complex. Dysplastic cerebellar gangliocytomas of adult patients occur in Cowden syndrome. Turcot syndrome overlaps with constitutional mismatch repair deficiency syndrome (CMMRD), which is associated with giant cell glioblastomas. Rhabdoid tumor predisposition syndrome (germline mutation of SMARCB1/INI1) is associated with atypical teratoid/rhabdoid tumors. Tumors arising in the setting of a cancer predisposition syndrome develop along specific genetic pathways. Some histopathological and immunohistochemical characteristics of these tumors may point toward such a syndrome. The diagnosis of a cancer predisposition syndrome is of tremendous importance to the patients and their families who require genetic counseling and long-term follow-up.

Genetic syndromes predisposing to paediatric brain tumours: the chicken or the egg?

Abstract Cancer in childhood is a disorder of growth and development. Up to 10% of patients diagnosed with cancer during childhood have a known underlying genetic predisposition syndrome. Affected individuals usually have multisystem involvement from the underlying syndrome and certain syndromes are associated with development of characteristic tumours with sites of predilection within the neuraxis. For the healthcare professionals involved with paediatric patients it is important to have basic knowledge of the cancer susceptibility syndromes. A holistic multidisciplinary approach is required for the overall management of the syndrome itself with specific recommendations for imaging surveillance and genetic counselling based on the pattern of inheritance and the relative risk of developing a tumour. Appropriate knowledge of these syndromes will help paediatricians manage and refer patients at risk to specialist neuro-oncology centres. A typical brain tumour diagnosis can also indicate certain underlying genetic disorders and examples of such tumours include optic pathway glioma, choroid plexus carcinoma and subependymal giant cell astrocytoma. A detailed family history can be helpful in identifying at risk patients and families as the typical clinical signs associated with the genetic condition are often not fully apparent in young children. This article focuses on well-known genetic diagnoses associated with or predisposing to childhood brain tumours. In some instances, the brain tumour diagnosis subsequently leads to the diagnosis of an underlying genetic syndrome.

Modeling Neurodevelopmental Deficits in Tuberous Sclerosis Complex with Stem Cell Derived Neural Precursors and Neurons.

Tuberous sclerosis complex (TSC) is a rare genetic disorder that is caused by mutations in TSC1 or TSC2. TSC is a multi-organ disorder characterized by development of non-malignant cellular overgrowths, called hamartomas, in different organs of the body. TSC is also characterized as a neurodevelopmental disorder presenting with epilepsy and autism, and formation of cortical malformations ("tubers"), subependymal giant cell astrocytomas (SEGAs), and subependymal nodules (SENs) in the patient's brain. In this chapter, we are going to give an overview of neural stem cell and neuronal development in TSC. In addition, we will also describe previously developed animal models of TSC that display seizures, autistic-like behaviors, and neuronal cell abnormalities in vivo, and we will compare them to disease phenotypes detected with human stem cell derived neuronal cells in vitro. We will describe the effects of TSC-mutations in different neural cell subtypes, and discuss the mitochondrial function, autophagy, and synaptic development and functional deficits in the neurons. Finally, we will review utilization of these human TSC-patient derived neuronal models for drug screeningto develop new treatment options for the neurological phenotypes seen in TSC patients.

Recombinant Tissue Plasminogen Activator Use in an Acute Stroke Patient With Tuberous Sclerosis

Tuberous sclerosis (TS) is an autosomal dominant disease known for over a century and recognized by characteristic hamartomatous lesions involving any organ. In this report, we are presenting a patient with TS who presented with acute embolic stroke and received tissue plasminogen activator (tPA) and had a mechanical thrombectomy (MT). She had a dramatic response without any hemorrhagic complications. She is a 68-year-old Caucasian woman with the past medical history of TS since childhood who presented to the hospital with symptoms of left middle cerebral artery (MCA) syndrome (right-sided weakness, sensory loss, right facial droop, aphasia, hemianopia, and dysarthria). National Institute of Health Stroke Scale (NIHSS) score was 19. Head computed tomography (CT) was negative for any acute abnormality except cortical tubers, subependymal ventricular calcification. CT angiography of the head and neck showed proximal occlusion of the left internal carotid artery. After ruling out all exclusion criteria, the patient received tPA and had an MT with complete reperfusion (thrombolysis in cerebral infarction (TICI) 3). Brain magnetic resonance imaging (MRI) showed an acute stroke in the multivessel territories (bilateral parietal cortices, the left lentiform nucleus, medial left temporal lobe, left thalamus, and right occipital lobe) suggestive of an embolic phenomenon and did not show any hemorrhagic complication. TS patients are at increased risk of intracerebral hemorrhage either in the setting of vascular malformation or due to hemorrhage into the subependymal giant cell astrocytoma. The best explanation for the latter could be secondary to elevated venous pressure from increased intracranial pressure. Fortunately, our TS patient who presented with acute ischemic stroke was within the window and received tPA and MT. The patient not only did not have any hemorrhagic side effects afterward but also had a significant improvement in her neurologic symptoms. To our best knowledge, this is the only case report of tPA administration in a TS patient. Moreover, we need more case reports to evaluate the safety of tPA in these patients. J Neurol Res. 2020;10(4):140-143 doi: https://doi.org/10.14740/jnr595