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The phakomatoses are a group of genetic and acquired disorders characterized by neurologic, cutaneous, and often ocular manifestations, thus commonly referred to as neurocutaneous syndromes. In several of these conditions the underlying genetic pathophysiology has been elucidated, which will continue to play an important role in advancing therapeutic techniques. This article focuses on several examples of such neurocutaneous syndromes, with special attention to the relevant neurosurgical considerations of these patients.

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.

Objective We studied the accuracy of the radiologic diagnosis of lateral ventricular masses in children ( Methods In this retrospective study, data were collected from children with lateral ventricular masses managed in our unit between 2001 and 2016. There were 43 patients (26 boys and 17 girls; mean age, 12.1 years; range, 8 months to 20 years). Magnetic resonance imaging was available for 36 patients, whereas in 7 patients only a contrast-enhanced computed tomography scan was available. The images were read independently by 3 radiologists, who were blinded to the pathology. Two differential diagnoses were offered for each patient. The agreement between the 3 radiologists was calculated using the Fleiss κ statistic. Results The common pathologic diagnoses were subependymal giant cell astrocytoma (SEGA) (20.9%), low-grade astrocytoma (16.3%), high-grade astrocytoma (9.3%), choroid plexus papilloma (9.3%), and meningioma (9.3%). The sensitivity, specificity, and accuracy of the radiologic diagnoses were 62%, 96.7%, and 94.2%, respectively. Low-grade tumors such as low-grade gliomas, SEGAs, choroid plexus papillomas, and meningiomas were diagnosed with a high level of accuracy. High-grade gliomas, choroid plexus carcinomas, and other malignant neoplasms were difficult to diagnose on imaging. Cavernous angiomas were also difficult to diagnose. There was only fair agreement between the 3 radiologists (Fleiss κ = 0.24). Conclusions The pathologic spectrum of lateral ventricular tumors in children is wide, and identifying the pathology on imaging is difficult for malignant tumors. Benign tumors such as SEGAs, low-grade astrocytomas, and choroid plexus papillomas are relatively easier to diagnose. There is significant interobserver variability in the radiologic diagnosis of these tumors.

Neurofibromatosis type-1 is a familial genetic syndrome associated with a predisposition to develop peripheral and central nervous system neoplasms. We have previously reported on a subset of gliomas developing in these patients with morphologic features resembling subependymal giant cell astrocytoma, but the molecular features of these tumors remain undefined. A total of 14 tumors were studied and all available slides were reviewed. Immunohistochemical stains and telomere-specific FISH were performed on all cases. In addition, next-generation sequencing was performed on 11 cases using a platform targeting 644 cancer-related genes. The average age at diagnosis was 28 years (range: 4–60, 9F/5M). All tumors involved the supratentorial compartment. Tumors were predominantly low grade (n = 12), with two high-grade tumors, and displayed consistent expression of glial markers. Next-generation sequencing demonstrated inactivating NF1 mutations in 10 (of 11) cases. Concurrent TSC2 and RPTOR mutations were present in two cases (1 sporadic and 1 neurofibromatosis type-1-associated). Interestingly, alternative lengthening of telomeres was present in 4 (of 14) (29%) cases. However, an ATRX mutation associated with aberrant nuclear ATRX expression was identified in only one (of four) cases with alternative lenghtening of telomeres. Gene variants in the DNA helicase RECQL4 (n = 2) and components of the Fanconi anemia complementation group (FANCD2, FANCF, FANCG) (n = 1) were identified in two alternative lenghtening of telomere-positive/ATRX-intact cases. Other variants involved genes related to NOTCH signaling, DNA maintenance/repair pathways, and epigenetic modulators. There were no mutations identified in DAXX, PTEN, PIK3C genes, TP53, H3F3A, HIST1H3B, or in canonical hotspots of IDH1, IDH2, or BRAF. A subset of subependymal giant cell astrocytoma-like astrocytomas are alternative lenghtening of telomere-positive and occur in the absence of ATRX alterations, thereby suggesting mutations in other DNA repair/maintenance genes may also facilitate alternative lenghtening of telomeres. These findings suggest that subependymal giant cell astrocytoma-like astrocytoma represents a biologically distinct group that merits further investigation.

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.

Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) that has been approved by the US Food and Drug Administration for the treatment of subependymal giant cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC). Retinal hamartomas, which are one of the major diagnostic features of TSC, tend to remain stable or gradually progress in the natural history of the disease. We report 2 patients with TSC treated with everolimus for SEGA in whom fundus photographs and spectral domain optical coherence tomography demonstrated regression of previously documented multiple retinal hamartomas in all 4 eyes.

Tuberous sclerosis complex (TSC) is a multisystem, autosomal dominant disorder with a wide clinical spectrum. The most common brain tumor associated with TSC is the low grade subependymal giant cell astrocytoma. Reports of high grade primary brain tumors in patients with TSC are rare. TSC1/2 mutation has been identified in glioblastoma (GBM) even though it probably does not increase the overall risk for GBM in patients with TSC. We present a 58-year-old patient with known TSC, admitted for new neurological symptoms, diagnosed with a large heterogeneous tumor involving most of the corpus callosum. Stereotactic needle brain biopsy confirmed the diagnosis to be GBM. Five previously reported similar cases are reviewed, reflecting diversity in clinical and radiological findings and indicating that a high index of clinical suspicion must be maintained in patients with TSC.

Introduction Subependymal giant cell astrocytoma (SEGA) is the most common central nervous system neoplasm in patients with tuberous sclerosis complex (TSC). Pathologic brain lesions include cortical tubers, subependymal nodules (SENs), subependymal giant cell tumors (SGCTs), and white matter abnormalities. SENs develop during foetal life in the subependymal wall of the lateral ventricles, are present in most patients with TSC, and are usually asymptomatic. The growth of SEN peaks at puberty and stops by the end of the third decade of life. Transformation of a SEN into a SEGA is usually a gradual process, of which the highest rate is in the first two decades of life. Case report The authors reports a family with SEN and SEGA in a mother and son with Tuberous Sclerosis complex. A 16-year-old male patient presented with progressive painless loss of vision with headache. A comprehensive clinical evaluation of the patient and his mother revealed clinical features characteristic of TSC. Family history was also suggestive of TSC. Neuroimaging revealed an enhancing left ventricular mass lesion located in the region of the foramen of Monro with mass effect. The lesion had radiographic characteristics of SEGA. Retrospective Neuroimaging of the patient’s mother also revealed multiple calcified discrete subependymal nodules. The patient underwent gross-total resection of the tumor. Tumor histology was consistent with SEGA. Conclusion To date, no radiographic features have been identified that will accurately predict which subependymal nodules will grow and require treatment. To our knowledge no reports of SEN and SEGA in a family members with clinical diagnosis of Tuberous Sclerosis has been reported in the literature till date. We thereby present a literature review of familial TSC and SEGA reports as well as look at radiological features that assist in predicting progression in SEGA and SENs.

Subependymal giant cell astrocytoma is a benign brain tumor mostly associated with tuberous sclerosis complex. However, it may be misinterpreted as other high-grade brain tumors due to the presence of large tumor cells with conspicuous pleomorphism and occasional atypical features, such as tumor necrosis and endothelial proliferation. In this study, we first investigated thyroid transcription factor-1 (TTF-1) expression in a large series of subependymal giant cell astrocytomas and other histologic and locational mimics to validate the diagnostic utility of this marker. We then examined TTF-1 expression in non-neoplastic brain tissue to determine the cell origin of subependymal giant cell astrocytoma. Twenty-four subependymal giant cell astrocytoma specimens were subjected to tissue microarray construction. For comparison, a selection of tumors, including histologic mimics (21 gemistocytic astrocytomas and 24 gangliogliomas), tumors predominantly occurring at the ventricular system (50 ependymomas, 19 neurocytomas, and 7 subependymomas), and 134 astrocytomas (3 pleomorphic xanthoastrocytomas, 45 diffuse astrocytomas, 46 anaplastic astrocytomas, and 40 glioblastomas) were used. Immunohistochemical stain for TTF-1 was positive in all 24 subependymal giant cell astrocytomas, whereas negative in all astrocytomas, gangliogliomas, ependymomas, and subependymomas. Neurocytomas were positive for TTF-1 in 4/19 (21%) of cases using clone 8G7G3/1 and in 9/19 (47%) of cases using clone SPT24. In the three fetal brains that we examined, TTF-1 expression was seen in the medial ganglionic eminence, a transient fetal structure between the caudate nucleus and the thalami. There was no BRAFV600E mutation identified by direct sequencing in the 20 subependymal giant cell astrocytomas that we studied. In conclusion, TTF-1 is a useful marker in distinguishing subependymal giant cell astrocytoma from its mimics. Expression of TTF-1 in the fetal medial ganglionic eminence indicates that subependymal giant cell astrocytoma may originate from the progenitor cells in this region.

Introduction The well-described entity of Subependymal Giant Cell Astrocytoma (SEGA) in the setting of Tuberous Sclerosis Complex (TSC) is profound in current literature. It has been described in children as well as adults with or without identifiable clinical presentations of tuberous sclerosis. To our knowledge there has not been any report of a negative genetic workup of Tuberous Sclerosis Complex in an adult patient presenting with an isolated SEGA. Case report We present a case of a 25-year-old female with no medical history who presented to the emergency room for headaches. Further workup included gadolinium enhanced MRI of the brain which revealed a homogenously enhancing mass in the left lateral ventricle with eccentric calcification and resultant obstructive hydrocephalus. A left frontal craniotomy with an interhemispheric transcallosal approach was taken for complete removal of the mass. Discussion Final pathological diagnosis was SEGA with suggestive cell population, positive GFAP and positive synaptophysin. Genetic testing included TSC1 (MLPA, DNA Sequencing) and TSC2 (MLPA, DNA Sequencing), which were all negative. The panel did not identify mutations associated with Tuberous Sclerosis. Conclusion Rare cases of isolated SEGA have been reported in patients who do not have typical features of tuberous sclerosis, and may represent minimal penetrance of the disease with an attenuated phenotype. Negative genetic testing, as demonstrated, can be seen in adults with isolated SEGA. With a negative genetic workup of TSC, regular follow up may still be necessary; however this may prove to be low yield for identifying any TSC features in the future.

Tuberous sclerosis complex is an autosomal-dominant, neurocutaneous, multisystem disorder characterized by cellular hyperplasia and tissue dysplasia. The genetic cause is mutations in the TSC1 gene, found on chromosome 9q34, and TSC2 gene, found on chromosome 16p13. The clinical phenotypes resulting from mutations in either of the 2 genes are variable in each individual. Herein, advances in the understanding of molecular mechanisms in tuberous sclerosis complex are reviewed, and current guidelines for diagnosis, treatment, follow-up, and management are summarized.

BACKGROUND: Subependymal giant cell astrocytoma is a brain tumor associated with tuberous sclerosis complex. There are two treatment options for subependymal giant cell astrocytomas: surgery or mammalian target of rapamycin inhibitor. The analysis of outcome of subependymal giant cell astrocytoma surgery may help characterize the patients who may benefit from pharmacotherapy. METHODS: Sixty-four subependymal giant cell astrocytoma surgeries in 57 tuberous sclerosis complex patients with at least a 12-month follow-up were included in the study. The tumor size, age of the patients, mutation in the TSC1 or TSC2 gene, indication for the surgery, and postsurgical complications were analyzed. RESULTS: The mean age of patients at surgery was 9.7 years. Mean follow-up after surgery was 63.7 months. Thirty-seven (57.8%) tumors were symptomatic and 27 (42.2%) were asymptomatic. Patients with TSC2 mutations developed subependymal giant cell astrocytoma at a significantly younger age than individuals with TSC1 mutations. Four patients (6.2% of all surgeries) died after surgery. Surgeryrelated complications were reported in 0%, 46%, 83%, 81%, and 67% of patients with tumors 4 cm, and bilateral subependymal giant cell astrocytomas, respectively, and were most common in children younger than 3 years of age. The most common complications included hemiparesis, hydrocephalus, hematoma, and cognitive decline. CONCLUSIONS: Our study indicates that subependymal giant cell astrocytoma surgery is associated with significant risk in individuals with bilateral subependymal giant cell astrocytomas, tumors bigger than 2 cm, and in children younger than 3 years of age. Therefore, tuberous sclerosis complex patients should be thoroughly screened for subependymal giant cell astrocytoma growth, and early treatment should be considered in selected patients.

BackgroundTuberous sclerosis complex is an autosomal dominant disorder predisposing to the development of benign lesions in different body organs, mainly in the brain, kidney, liver, skin, heart, and lung. Subependymal giant cell astrocytomas are characteristic brain tumors that occur in 10% to 20% of tuberous sclerosis complex patients and are almost exclusively related to tuberous sclerosis complex. Subependymal giant cell astrocytomas usually grow slowly, but their progression ultimately leads to the occlusion of the foramen of Monro, with subsequent increased intracranial pressure and hydrocephalus, thus necessitating intervention. During recent years, secondary to improved understanding in the biological and genetic basis of tuberous sclerosis complex, mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of subependymal giant cell astrocytomas, becoming an alternative therapeutic option to surgery.MethodsIn June 2012, an International Tuberous Sclerosis Complex Consensus Conference was convened, during which an expert panel revised the diagnostic criteria and considered treatment options for subependymal giant cell astrocytomas. This article summarizes the subpanel's recommendations regarding subependymal giant cell astrocytomas.ConclusionsMammalian target of rapamycin inhibitors have been shown to be an effective treatment of various aspects of tuberous sclerosis complex, including subependymal giant cell astrocytomas. Both mammalian target of rapamycin inhibitors and surgery have a role in the treatment of subependymal giant cell astrocytomas. Various subependymal giant cell astrocytoma–related conditions favor a certain treatment.

BackgroundTuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threatening with significant impact on cost and quality of life. Current surveillance and management practices are highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices.MethodsThe 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly.ResultsThe updated consensus recommendations for clinical surveillance and management in tuberous sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established.ConclusionsThe 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of tuberous sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important diagnostic implications and was charged with reviewing prevalence and specificity of diseaseassociated clinical findings and their impact on suspecting and confirming the diagnosis of tuberous sclerosis complex. RESULTS: Clinical features of tuberous sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of tuberous sclerosis complex in affected individuals.

Objectives The indications for surgery and outcomes of patients who underwent surgical removal of subependymal giant cell astrocytomas (SEGAs) in our institution between 2000 and 2011 were reviewed. Methods We reviewed the clinical details of 16 patients with a diagnosis of Tuberous Sclerosis Complex (TSC) who underwent surgery for SEGA in Bristol since 2000. We collected information on age, sex, epilepsy history and cognitive status. We reviewed the indications for surgery, age at surgery, surgical approach, and the size and location of the lesions. We analysed mortality, completeness of tumour resection, intraoperative blood transfusion, shunt placements, and surgical complications. Results 13 patients had surgery due to hydrocephalus. Increasing size of SEGA without hydrocephalus was an indication for surgery in two patients, and in one patient, the SEGA was removed because of its size and location at initial scan. 13 patients had complete tumour resection. One patient had tumour recurrence. Hydrocephalus failed to resolve or reoccurred in four patients post operatively necessitating shunt insertion. The surgical approach was transcortical in 14 patients and transcallosal in two. There was zero mortality in this series. There were no reports of cognitive decline or worsening epilepsy following surgery. Conclusion Surgery is a safe and effective treatment for SEGA. It is the authors' view that surgery remains the most appropriate treatment strategy for SEGAs that are amenable to surgery. More work needs to be undertaken to assess prospectively the neurocognitive impact of surgery, and the relative advantages of different surgical approaches.

Lateral ventricular neoplasms are rare, and account for 50% of all intraventricular tumors in adults and 25% in children. Although these neoplasms are easily detected with computed tomography (CT) and magnetic resonance imaging (MRI), both techniques are relatively unspecific in identifying the type of tumor. However, few imaging patterns are specific for a particular pathological process and useful conclusions can be made from the morphological appearance of the lesion, its location and enhancement pattern. The aim of this article was to review and illustrate the CT and MRI findings of a wide spectrum of tumors of the lateral ventricle. We reviewed choroid plexus tumors, meningioma, subependymal giant cell astrocytoma, central neurocytoma, and less frequent lesion such as lymphoma and metastases.

Background Although neuroendoscope is widely used, endoscopic removal of intraventricular solid tumors has rarely been reported. Most reported procedures were performed with special endoscopic instruments through the endoscope's working channel—intra-axial endoscopic procedures. We report two cases of combined intra-/extra-axial endoscopic procedures—intraventricular solid tumor resection for subependymal giant cell astrocytoma. Methods In 2007, two patients with subependymal giant cell astrocytoma with a long history of tuberous sclerosis underwent solely endoscopic, minimally invasive intraventricular tumor resection. Through a precoronal transcortical approach, intra-axial endoscopic techniques were used to biopsy tumors. After a 1- to 1.5-cm in diameter corridor was formed inside the frontal lobes, extra-axial endoscopic techniques were used to explore the tumors and resect them. During extra-axial procedures, microneurosurgical instruments were used around the endoscope. Results In both patients, gross total resection of the tumors was achieved safely. Pathologic diagnoses were subependymal giant cell astrocytoma. There were no complications from surgery, and no neurological deficits. Patients were doing well and shunt free during the 8-month postoperative follow-ups. Postoperative magnetic resonance images showed minimal approach-related trauma along the surgical corridor. Conclusions In the present report endoscopic minimally invasive neurosurgery (EMIN) was defined as procedures in which the endoscope was used independently as the only optical device, for both illumination and visualization. Depending on the relationship between surgical instruments and the endoscope, EMIN was classified as intra-axial and extra-axial procedures. EMIN is a completive, safe procedure for intraventricular subependymal giant cell astrocytoma.

Solitary fibrous tumor was first reported in the pleura; however, it has since been reported in many other locations. Solitary fibrous tumors of the central nervous system are uncommon and the intraventricular location is exceptional. To our knowledge, only eight cases of intraventricular solitary fibrous tumor have been reported. We describe a case of intraventricular solitary fibrous tumor.The imaging characteristics of intraventricular solitary fibrous tumors are nonspecific; the differential diagnosis should include other tumors that can affect the ventricular system such as meningioma, high grade glioma, metastasis, subependymoma, choroid plexus papilloma, ependymoma, subependymal giant cell astrocytoma, and neurocytoma. At histological study, immunohistochemical techniques allow solitary fibrous tumor to be differentiated from fibrous meningioma and hemangiopericytoma.

Glial tumors of the retina are rare. Most are syndrome associated and include pilocytic astrocytoma in neurofibromatosis type 1 and subependymal giant cell astrocytoma in tuberous sclerosis complex. Acquired, more conventional, diffuse astrocytomas are less frequent. Ependymoma is exquisitely rare. Herein, we report the clinicopathologic features of the second case of retinal ependymoma. The tumor was sporadic in occurrence and unilateral, low grade, and of cellular type. Its chronic course and large size prompted an initial pathologic diagnosis of "massive retinal gliosis." The literature regarding retinal glial neoplasia including ependymoma as well as the so-called massive retinal gliosis is discussed.

Neuroimaging data of lateral ventricle gliomas and central neurocytomas diagnosed in one institution were reviewed and compared to the corresponding literature data. CT and MRI imaging characteristics of the two tumour types are rather different, both in reported cases as well as in our material. In our series ventricular ependymomas (eight cases) were mostly hyperdense with pronounced contrast uptake. Thirteen subependymomas were hypodense, mostly without enhancement, but occasionally mild or moderate enhancement was noted. Eight subependymal giant cell astrocytomas also displayed hypodense, rarely hyperdense or mixed imaging characteristics, and always showed significant degree of contrast enhancement. Nineteen central neurocytomas showed hypo- or mixed density, but mostly mild to moderate enhancement. Ependymomas and anaplastic astrocytomas and glioblastomas followed the characteristics of the similar extraventricular ones. In our series low-grade astrocytomas, WHO I-II [Louis DN, Ohgaki H, Wiestler OD, Canevee WK. WHO classification of tumours of the central nervous system. Lyon: International Agency for Research on Cancer; 2007] were hypodense without contrast uptake. Our data support those of previous studies in that MRI has been found to be superior to CT for a more precise imaging of lateral ventricle gliomas. However, it is of note that for the verification of an intraventricular tumour CT is also satisfactory. Survival data were available in 65 cases, which have confirmed a favourable outcome in most of the patients with subependymoma, subependymal giant cell astrocytoma, central neurocytomas or pilocytic astrocytoma. Survival of patients with other types of glial tumour was similar to that of patients with a similar tumour, but in an extraventricular localisation.

Ependymomas account for 3-9% of all neuroepithelial tumors. A peculiar variant of ependymoma known as "giant cell ependymoma" ("GCE") is especially rarely reported, it may pose some difficulties for the diagnosing neuropathologist. Here we present a case of a giant cell ependymoma occuring in a 17-year-old patient with the history of 2-year recurrent headaches and a 1-month history of vision impairment. CT scanning demonstrated a mass in the left occipital lobe, arising from the occipital horn of the lateral ventricle. Histological, immunohistochemical and electron microscopic findings were consistent with high-grade ependymoma. Especially striking was the presence of bizzare pleomorphic giant cells which predominated in the tumor tissue. As a result the diagnosis of GCE was established. This type of neoplasm necessitates, at least in theory, differentiation with anaplastic oligodendroglioma, clear cell ependymoma, pleomorphic xanthoastrocytoma, giant cell glioblastoma, and subependymal giant cell astrocytoma. To date giant cell ependymomas (GCEs) were reported in seven cases in the literature. To the best of our knowledge this is the 8th case in the literature. In spite of apparently "worrisome" histology GCE seems to be a neoplasm with a relatively good prognosis.

Subependymal giant cell astrocytomas are one of the three major intracranial lesions found in tuberous sclerosis complex. Subependymal giant cell astrocytomas are typically slow-growing tumors of mixed glioneuronal lineage which can become aggressive and cause obstructive hydrocephalus usually in older children and adolescents. Neonatal subependymal giant cell astrocytomas are extremely rare, and their natural history and prognosis are poorly understood. This report investigates an extremely large neonatal subependymal giant cell astrocytoma which was initially identified in utero at 19 weeks of gestation in a high-risk pregnancy with no family history of tuberous sclerosis complex.

Tuberous sclerosis is a phakomatosis with central nervous system manifestations characterized by 4 lesions detectable on neuro-imaging: tubers, white matter abnormalities, subependymal nodules and subependymal astrocytomas. The first three are benign lesions composed of by identical cytological lesions varying only in size and location. At CT, enhancement of subependymal nodules is usually considered as evidence of transformation to subependymal giant cell astrocytoma. This latter poses the problem of its relative benignity: hydrocephalus source of morbidity or even mortality. From a series of 22 cases, the authors review the characteristics of these abnormalities.

Subependymal giant cell astrocytoma (SEGA) is a unique brain tumor arising in tuberous sclerosis complex (TSC), an autosomal dominant inherited phacomatosis. There are several case reports of solitary SEGA without any other manifestations of TSC. Usually these cases are thought to be forme fruste of TSC due to somatic mosaicism. However, no previous reports have used molecular methodology to fully investigate mutations in TSC genes or the possibility of somatic mosaicism. Here, we report a 20-year-old woman with a brain tumor. Pathological diagnosis was consistent with SEGA, but comprehensive clinical screening found no other lesions indicative of TSC. Molecular analysis of the tumor revealed loss of heterozygosity and allelic mutation (5228G>A, R1743Q) of TSC2. To detect the small fraction of mosaic mutation in somatic cells, we developed a highly sensitive new method: triple-nested polymerase chain reaction-restriction fragment length polymorphism. The identical TSC2 missense mutation was not detected in any other tissues from the same patient, including peripheral blood, buccal mucosa, urinary sediment, nail, and hair. According to these results, this patient should be considered as having SEGA that developed from two somatic hit mutations in TSC2, rather than being a TSC2 patient with a very small fraction of somatic mosaicism.

The clinical and neuroimaging features of 20 patients with lateral ventricular tumours located around the foramen of Monro were reviewed retrospectively with special emphasis on the differential diagnoses. Histologic types were: eight neurocytomas, four subependymal giant cell astrocytomas (SGCAs), three subependymomas, two fibrillary astrocytomas, and one each of pilocytic astrocytoma, malignant astrocytoma and malignant teratoma. The mean age of the patients with neurocytoma was 29.6 years, with SGCA 13.3 years and with subependymoma 55.3 years. All tumours appeared nodular in shape, and on computed tomography (CT) neurocytomas were either isodense or highdense with the brain, while all subependymomas and SGCAs were lowdense. Calcification was observed in two SGCAs, and one neurocytoma. Five neurocytomas and all four SGCAs showed mild to moderate contrast enhancement, while all three subependymomas showed either no, or scarce, enhancement. Magnetic resonance imaging (MRI) studies were available in 10 patients, with the signal characteristics of four neurocytomas and three SGCAs being nonspecific, while two subependymomas were both hypointense on T1-weighted images and hyperintense on T2-weighted images. Thus important features for differential diagnosis included age of the patient and density on precontrast CT. In this series, either an extensive excision of the tumour or a partial removal, thus relieving the obstruction of the foramina of Monro, usually provided long term survival, with 18 patients surviving a mean of 10.8 years.

Background Direct surgical resection remains the standard treatment for patients with tuberous sclerosis complex (TSC) with a large subependymal giant cell astrocytoma (SEGA). Rapamycin or everolimus is seldom used in these patients because of the risk of increased intracranial pressure and possibility of sudden death. Case Descriptions Three patients with TSC and a large intracranial SEGA received oral rapamycin (0.5 mg/day) or everolimus (2.5 mg/day) before surgery for tumor resection. After mTOR inhibitor therapy, computed tomography scans and magnetic resonance imaging revealed tumor reduction. Tumor bleeding was easy to control during surgery, and the border between tumor and surrounding brain tissue was clearly differentiated. Analysis of postsurgical tumor specimens showed low blood density and focal necrosis. Conclusions Preoperative mTOR inhibitors could be a potentially novel treatment modality in large TSC-SEGA with hydrocephalus. In this series, mTOR inhibitors were not only safe and well tolerated, but also beneficial for tumor resection.

The clinical history, neuroimaging features, treatments, and outcome of 4 patients with histologically verified subependymal giant cell astrocytomas (SEGA) were retrospectively reviewed. The average age at the time of surgery was 13.3 years. Headache re lated to raised intracranial pressure was the first and only sign in 2 patients, with the remaining 2 being admitted because of sequential neuroimaging studies over several years revealing the growth of 'subependymal nodules' into intraventricular tumours. In each case the tumour was in the region of Monro's foramen and was associated with ventricular dilatation. On computed tomography (CT), multiple subependymal nodules were found in 3 patients, and these well circumscribed isodense SEGAs were markedly enhanced by contrast medium. On magnetic resonance imaging (MRI), which was obtained in 3 patients, 2 SEGAs were isointense with the cerebral cortex and one with the white matter on T 1 -weighted images, and on T 2 -weighted images, 2 were isointense with the cortex and one with the white matter. At surgery the tumours appeared to originate from the inferolateral wall of the lateral ventricle in the region of the head of the caudate nuclei. Total macroscopic remova l was achieved in 3 patients, and subtotal removal in one patient. Follow up ranged from 4.6 to 13.2 years, and all patients have exhibited similar physical and mental conditions to preoperative. So far there has been no evidence of any recurrences. The diagnosis and thesurgical indications for SEGA are discussed, with periodic monitoring with neuroimaging studies being recommended even for asymptomatic patients with 'subependymal nodules'.

Subependymal giant cell astrocytomas are benign tumors that constitute one of the primary features of tuberous sclerosis. Two infants with tuberous sclerosis had very unusual subependymal giant cell astrocytomas, confirmed on biopsy in one of the infants. In both cases, contrast-enhanced cranial magnetic resonance imaging suggested a calcified intra-axial mass with diffuse basal ganglia involvement extending into the lateral ventricle. Computed tomography confirmed calcification in both cases. The first patient had right temporal lobectomy for intractable epilepsy. Biopsy of the basal ganglia lesion in that case suggested subependymal giant cell astrocytoma. In infants, subependymal giant cell astrocytomas can present with unusual morphology and may feature diffuse basal ganglia involvement and severe calcification.

In this report, we describe a case of subependymal giant cell astrocytoma in a patient lacking clinical symptoms of tuberous sclerosis. The absence of any features of tuberous sclerosis initially dissuaded us from including subependymal giant cell astrocytoma in our differential diagnosis.

Objective To report an unusual case of giant cell astrocytoma of the retina. Design Case report. Intervention A 10-month-old girl with tuberous sclerosis was found to have bilateral astrocytic hamartomas, the right eye being prominently involved by elevated and pedunculated lesions. At 7 years of age, she had posterior subcapsular cataract, retinal detachment, and subretinal exudation develop in the right eye. At 12 years of age, her blind, painful right eye had to be enucleated because of neovascular glaucoma and a spontaneous scleral perforation. Results Histopathologic examination showed that the entire vitreous cavity was filled with a mixture of tumor, granulation tissue, and necrotic debris. Part of the tumor was composed of spindle-shaped glial cells. The remainder was composed of large gemistocytic cells that contained large atypical nuclei and copious amounts of cytoplasm, which was intensely eosinophilic in some areas. The tumor contained foci of necrosis and rare mitotic figures. It had infiltrated the parenchyma of the retrolaminar nerve and extended to the surgical margin. Areas of unequivocal choroidal invasion were also identified. The tumor cells were intensely immunoreactive for neuron-specific enolase and S-100 protein. In contrast, glial fibrillary acidic protein was only minimally positive. Conclusions The histologic and immunohistochemical features of this retinal tumor resemble those of subependymal giant cell astrocytoma, a characteristic lesion in tuberous sclerosis. Although this unusual giant cell astrocytoma of the retina had atypical histopathologic features and local aggressive behavior, the systemic prognosis was excellent.

Subependymal giant cell astrocytoma (SEGA) is an uncommon tumor that usually occurs in the setting of tuberous sclerosis (TS) syndrome. We report a rare case of an intratumoral and a small intraventricular hemorrhage complicating a SEGA in an adult patient without any signs of TS. Although pre-operative CT and MRI findings for the tumor were typical of SEGA, SEGA was not considered in the differential diagnosis because the patient was lacking any symptoms of TS. This is the second report of intraventricular and intratumoral hemorrhage complicating a SEGA and the first case in which these complications occurred in an adult patient in whom there was no previous suspicion of systemic disease.

Five children with tuberous sclerosis and intracranial tumors were surgically treated at Neurosurgery Department of Hacettepe University School of Medicine. Two of the five patients presented with the giant cell astrocytoma filling the third ventricle. Direct surgical intervention and tumor removal was carried out in all four patients (three with a total surgical resection and one with a subtotal resection) and cerebrospinal fluid shunting procedure in one. Histopathological examination revealed giant cell astrocytomas in four patients. Postoperatively, one died and the rest four patients survived with minor focal neurologic difficulties. The surgical results and the changing concepts in the treatment of tuberous sclerosis are discussed and the literature is reviewed.

To assess the long-term safety of everolimus in young children with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA).EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (EXIST-1) was a multicenter, randomized, double-blind phase 3 study with an open-label extension evaluating the efficacy and tolerability of everolimus in patients with TSC-associated SEGA. Everolimus was initiated at 4.5 mg/m(2)/day and titrated to blood trough levels of 5-15 ng/mL. Post hoc analysis of safety data (adverse events [AEs]) was performed in a subgroup of patients aged3 years at everolimus initiation.Eighteen patients (median age 1.82 years) were included; 16 were still receiving everolimus at the analysis cut-off date of January 11, 2013. Median everolimus exposure was 31.1 months (range, 11.5-39 months). One patient discontinued treatment because of AEs (ie, Acinetobacter bacteremia, increased blood alkaline phosphatase, and viral infection). AEs were reported in all patients, but events were mostly grade 1/2 in severity; 12 patients (66.7%) experienced grade 3 events, and 2 patients (11.1%) reported grade 4 events. The most common AEs were stomatitis, cough, pharyngitis, and pyrexia; no new safety issues were identified in this population. Serious AEs were reported in 50% of patients; these were suspected to be medication related in 4 patients (22.2%).Everolimus appears to be a safe therapeutic option for patients aged3 years with TSC-associated SEGA. The small sample size in this subpopulation limits interpretation of the results; additional studies in the pediatric population are needed and are underway.ClinicalTrials.gov: NCT00789828.

Of the 355 patients with tuberous sclerosis complex (TSC) examined at the Mayo Clinic, 49 had died (9 of causes other than TSC). We attempted to determine what pattern of organ involvement occurred most often in the 40 patients who died of TSC. One baby died of cardiac failure due to cardiac rhabdomyomas, and one child died of rupture of an aneurysm of the thoracic aorta. Eleven patients died of renal disease, which was the commonest cause of death. Ten patients died as a result of brain tumors, and four patients (who were 40 years of age or older) died of lymphangiomyomatosis of the lung. Thirteen patients with severe mental handicaps died of either status epilepticus or bronchopneumonia; in all but one of these patients, the only source of information was the death certificate. Survival curves show a decreased survival for patients with TSC in comparison with that for the general population. Patients with TSC need lifelong follow-up for early detection of potentially life-threatening complications.

Background Tuberous sclerosis complex is a heritable multisystem disorder associated with genes involved in the formation of a tumor-suppressor complex acting through the Ras homologue enriched in brain protein to limit activation of the mammalian target of rapamycin complex I. Mutations in these genes result in enhanced mammalian target of rapamycin signaling and may cause neurological manifestations including brain tubers, subependymal nodules, and subependymal giant cell astrocytomas. These astrocytomas are tumors that arise near the foramen of Monro and may lead to obstructive hydrocephalus. Standard therapy has been surgical resection. More recently, mammalian target of rapamycin inhibitor, everolimus, has been approved for treatment after demonstration of efficacy in prospective clinical trials. Methods We report a 15 year-old girl with tuberous sclerosis complex who proceeded to surgical resection of her subependymal giant cell astrocytoma after 3 months of treatment with mammalian target of rapamycin inhibition. We compared her subependymal giant cell astrocytoma tissue specimen with 12 untreated subependymal giant cell astrocytomas accessed from The Hospital for Sick Children in Toronto, Canada. Results This girl's histopathological findings were consistent with subependymal giant cell astrocytomas with no exposure to mammalian target of rapamycin inhibitors. There were no major differences identified on immunohistochemistry at targets downstream of mammalian target of rapamycin complex 1 or in neighboring signaling pathways. The majority of cells were reactive to glial fibrillary acidic protein, mitogen-activated protein kinase, phospho-S6, caspase 3 (95% positivity), and NP-1. Conclusion In this one individual, rapamycin therapy did not change the histopathological characteristics of subependymal giant cell astrocytoma. Mammalian target of rapamycin inhibition involves complex signaling pathways inducing subependymal giant cell astrocytoma shrinkage. However, its effect is not easily characterized within tumor tissue.

Objective Everolimus For Fast Expanded aCcess in TSC SEGA (EFFECTS) study was designed to provide early access to everolimus for patients with SEGA associated with TSC and to further assess the safety and efficacy of everolimus in a real-world setting. Methods In this phase 3b, multicenter, expanded access study, patients ≥3 years of age with a definite diagnosis of TSC, with at least 1 SEGA lesion identified by MRI or CT scan received once daily everolimus, the dose of which was adjusted to attain a trough level of 5–15 ng/mL. Safety assessments included the collection of adverse events (AEs) and serious AEs (SAEs), with their severity and relationship to everolimus. Efficacy evaluation (secondary objective) was based on the best overall response at the end of the study. Results Overall, 100 of 120 (83.3%) patients completed the study. Median age of patients was 11 years (range 1–47); median daily dose of everolimus was 5.82 mg (range 2.0–11.8); median duration of exposure was 56.5 weeks (range 0.3–130). Overall, AEs were reported in 89 (74.2%) patients. The most common AEs were aphthous stomatitis (18, 15.0%), pyrexia (18, 15.0%), bronchitis (11, 9.2%), and stomatitis (10, 8.3%). Grade 3 and 4 AEs were reported in 25 (20.8%) and 3 (2.5%) patients, respectively. The most frequent grade 3 AE was stomatitis (4, 3.3%). A total of 62 (51.7%) patients had suspected drug-related AEs, of which 15 (12.5%) had grade 3 or 4 AEs. In 8 (6.7%) patients, AEs caused drug discontinuation. A total of 81 (67.5%) patients had a partial response, 35 (29.2%) had a stable disease, and 1 (0.8%) had progressive disease. Response was unknown in 3 (2.5%) patients. Conclusion Results confirm the acceptable safety profile and further support the efficacy of everolimus in patients with SEGA associated with TSC, in a real-world setting.

Objectives To assess magnetic resonance imaging (MRI) findings in a group of 20 children below the age of 18 years diagnosed with tuberous sclerosis (TS). Methods The age of imaging and period of follow up, MRI characteristics of cortical tubers, subependymal nodules and other findings were recorded. Results Male/Female ratio was 6/14. Age at first imaging was 5 months to 18 years. Nine patients had follow-up imaging after 5 months–8 years. Seven of them were stable. One patient underwent tuber resection and temporal lobectomy. One patient had a partially calcified 2×1.5 cm subependymal giant cell astrocytoma which showed cystic degeneration and growed into 3×5.5 cm size on follow up. Six of all had cranial tomography. None had spinal imaging. Cortical tubers were mostly seen in frontal and parietal lobes. 2 patients had cerebellar tubers which were calcified. Ten patients had cortical cystic degeneration, 12 had calcification and 2 had Gadolinium enhancement in cortical tubers. Radial band was present in all but one. Subependymal nodules were mostly located around corpus of lateral ventricles and adjacent to foramen Monro (13/19). Amount of subependymal nodules ranged between 3–15 with a size of 2–9 mm. Seven patients had Gadolinium enhancement and 15 had calcification in subependymal nodules. One patient did not have subependymal nodules. In this study group 12/20 patients had enlarged perivascular space. Although 9/20 had thin corpus callosum and 12/20 had enlarged ventricles, only one patient showed cerebral atrophy. Conclusion We observed that in our patients quantity of cortical tubers in parietal lobes were similar to frontal lobes. 2/20 (10%) patients showed tubers in cerebellum. 60% revealed enlarged perivascular spaces which may be interesting to study in larger groups of TS patients.

Ependymomas are central nervous system (CNS) glial tumours thought to be derived from ependymal lining cells in the ventricles or spinal cord. The 2007 WHO classification of CNS tumours recognises three grades of ependymoma and several subtypes. 1 Giant cell ependymoma is a rare variant of ependymoma characterised by bizarre tumour giant cells with a variable component of more typical ependymoma. It has been described largely as isolated case reports and small series since its first recognition in 1996. 2 Giant cell ependymoma may be either WHO grade II or grade III. It has been described in variety of sites, including: spinal cord, cerebellum, the suprasellar region and cerebral hemispheres. We describe a case of giant cell ependymoma of the third ventricle occurring in a previously healthy 7 year old girl. The morphological features, immunohistochemical findings and ultrastructural features are discussed. As this ependymal subtype is not widely known, it may be confused with several other tumours including: pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, giant cell glioblastoma and atypical teratoid/rhabdoid tumour (ATRT). The differential diagnosis is discussed as confusion with these other entities may have significant treatment and prognostic implications making recognition of this rare ependymoma subtype vital.

1274 www.thelancet.com Vol 381 April 13, 2013 tuberous sclerosis and associated subependymal giant cell astrocytoma (SEGA). Such results justifi ably buoy some hope in the use of inhibitors of the mammalian target of rapamycin (mTOR) for the treatment of SEGAs, yet could relay an incomplete picture. As in all of medicine, providers must weigh the known risks and benefi ts of each proposed intervention within the context of the natural history of each disease. One of the more concerning complications of SEGAs include the development or worsening of hydrocephalus, which often requires treatment in the form of neurosurgical shunt placement. Although hydrocephalus was an inclusion criterion, and relative ventricular size was followed up throughout the study, Franz and colleagues do not specify the proportion of patients within the total everolimus cohort, relative to placebo, who either independently developed new, worsening, or improved hydrocephalus or who required shunt placement. These data, which were reported in an earlier, similarly designed, single-institution study on everolimus use in SEGAs, would be of vital importance to neuro-oncologists as they weigh the relative risks and benefi ts of everolimus. Additionally, a more uniform approach to the assessment of hydrocephalus, with standardised ventricular measurements such as the Evans ratio to defi ne hydrocephalus rather than the use of variable qualitative assessments, might further strengthen future studies to defi ne the eff ect of everolimus on patients with tuberous sclerosis and SEGA.

Ganglioglioma is a tumour of the central nervous system composed of an admixture of dysplastic nerve cells resembling pleomorphic ganglion cells, and glial elements which may be astrocytic and/or oligodendroglial in appearance. Differential diagnoses include subependymal giant cell astrocytoma associated with tuberous sclerosis and entrapment of normal neurones by astrocytoma. Review of hospital files over a 14 year period revealed 12 cases. The patients were aged between 9 months and 16 years, all suffered epilepsy refractory to medical treatment, for up to 8 years, the majority of whom obtained at least partial relief from symptoms after complete or partial resection. CT and NMR scans were of prime use in localisation of tumour. Calcification was noted pre-operatively in 33% of cases. Histologically 11 tumours included grade I astrocytic elements and one grade 2. All included large ganglion cell-like elements and in two cases perivascular small cells proven immunohistochemically to be lymphocytes were present. In 50% of cases the ganglion cell element stained for vimentin. Other antibodies including GFAP, NSE and S100 provided no further specific information. Prognosis is determined by the grade of astrocytic component. If this is of low grade then a complete or even partial excision may provide symptomatic relief from seizures, as was demonstrated in our cases. Post-operative radiotherapy is reserved for tumours with a high grade astrocytic element. If excision is incomplete slow regrowth, return of original symptoms and prolonged survival are the rule.

The distribution of the glial fibrillary acidic protein (GFAP) was investigated in sections of 131 paraffin-embedded brain neoplasms obtained at surgery or at autopsy. The unlabeled antibody immunoperoxidase (peroxidase-antiperoxidase, PAP) method was used. Equally good results were obtained from 17-year-old material and from recent material derived at surgery or autopsy and fixed with Bouin fluid or phosphate-buffered formalin. The perikaryons and processes of reactive astrocytes showed the most intense stain for GFAP. Positive reaction to antibody against GFAP of varying intensity was demonstrated in astrocytomas of various grades of malignancy (32 of 32), glioblastoma multiforme (10 of 10), subependymal giant cell astrocytoma (1 of 1), ependymoma (2 of 10), subependymoma (4 of 4), and astrocytes in mixed neoplasms (8 of 8). In two neoplasms diagnosed as malignant astrocytomas and in four neoplasms diagnosed as glioblastoma multiforme, GFAP stain was limited to a few neoplastic cells. Usually the stain was more intense over processes than in perikaryons, with the exception of gemistocytic astrocytomas and the giant cells in glioblastoma multiforme, which showed an equally, intense stain over perikaryons and processes. The periphery of Rosenthal fibers was intensely positive for GFAP. In astrocytic neoplasms the number of GFAP-positive cells and the intensity of the stain were inversely proportional to the degree of malignancy. In the following neoplasms the reaction for GFAP was negative: oligodendroglioma (3), oligodendroblastoma (I), medullo-blastoma (3), medulloepithelioma (1), neuroblastoma (1), pineocytoma (1), typical teratoma of the pineal (1), fibrosarcoma (1), pituitary adenoma (2), craniopharyngioma (1), chordoma (1), chemodectoma of globus jugulare (1), metastatic carcinoma (17), and lymphoma (8). In one of 18 meningiomas, endogenous peroxidase activity was seen in mast cells. All meningiomas studied were negative for GFAP. In one of six neurinomas a positive reaction for GFAP was detected over processes. The authors concluded that the immunostain for GFAP is useful in the diagnoses of astrocytic neoplasms and of mixed gliomas.