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MEK inhibitors (MEKi) represent innovative and promising treatments for managing manifestations of neurofibromatosis type 1 (NF1). To mitigate potential ophthalmic side effects, such as MEKi-associated retinopathy (MEKAR), patients undergoing MEKi therapy routinely receive ophthalmology evaluations. Our study aims to assess the necessity of this regular screening within a predominantly pediatric NF1 population by examining the occurrence of ocular adverse events (OAE). A retrospective study evaluated 45 NF1 patients receiving MEKi. Inclusion criteria included baseline and follow-up examinations following the initiation of MEKi therapy. At each assessment, a comprehensive eye evaluation was performed, comprising a dilated fundus examination, ocular coherence tomography of the macula and nerve fiber layer, and Humphrey visual field testing. Twenty-six patients, with an average age of 13 years (range 2–23 years) and an average follow-up duration of 413 days were included in the analysis. Three different MEKi were used: selumetinib (77%), trametinib (23%), and mirdametinib (4%). None of the patients experienced retinopathy at any point during the study. Some patients had pre-existing optic neuropathies (27%), but no instances of nerve changes occurred after commencing MEKi therapy. Four patients (15%) exhibited symptoms of dry eye, all of which were effectively managed with topical lubrication. [ABSTRACT FROM AUTHOR]

Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines, chemokines) elaboration. Their common pathobiology raises the intriguing possibility that brain injury could create a tissue microenvironment permissive for tumor formation. Leveraging several murine models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome and two experimental methods of brain injury, we demonstrate that both optic nerve crush and diffuse traumatic brain injury induce optic glioma (OPG) formation in mice harboring Nf1-deficient preneoplastic progenitors. We further elucidate the underlying molecular and cellular mechanisms, whereby glutamate released from damaged neurons stimulates IL-1β release by oligodendrocytes to induce microglia expression of Ccl5, a growth factor critical for Nf1-OPG formation. Interruption of this cellular circuit using glutamate receptor, IL-1β or Ccl5 inhibitors abrogates injury-induced glioma progression, thus establishing a causative relationship between injury and tumorigenesis. [ABSTRACT FROM AUTHOR]

In this paper, the authors present a clinical picture of the diagnosis and current treatment regimens of optic pathway glioma in the pediatric population, with an emphasis on the role of an ophthalmic diagnosis in the differentiation and monitoring of lesions. Glioma is the most common optic nerve tumor in children. Material: Articles in PubMed, Scholar and Website were reviewed, taking into account current standards of management related to sporadic or NF1-related optic glioma, epidemiology, location, course of the disease, clinical manifestations, histological types of the tumor, genetic predisposition, diagnostic ophthalmic tests currently applicable in therapeutic monitoring of the tumor, neurological diagnosis, therapeutic management and prognosis. The importance of current screening recommendations, in line with standards, was emphasized. Results: Glioma occurs in children most often in the first decade of life. Initially, they may be asymptomatic, and clinically ophthalmic changes are associated with the organ of vision or with systemic changes. Gliomas associated with the NF1 mutation have a better prognosis for sporadic gliomas. Diagnosis includes radiological imaging methods/MRI/ophthalmology/OCT and visual acuity log MAR assessment. The basis of treatment is clinical observation. In the case of disease progression, surgical treatment, chemotherapy and targeted therapy are used. Conclusion: Further research into novel techniques for detecting gliomas would allow for early monitoring of the disease. [ABSTRACT FROM AUTHOR]

The sphenoid ridge approach (SRA) was initially described as a surgical technique for treating vascular pathologies near the Sylvian fissure. However, limited studies have systematically explored the use of skull base techniques in pediatric patients. This study investigated an extended variation in the sphenoid ridge approach (E-SRA), which systematically removed the pterion, orbital walls (roof and lateral wall), greater sphenoid wing, and anterior clinoid process to access the base of the skull. Objective: This report aimed to evaluate the advantages of the extradural removal of the orbital roof, pterion, sphenoid wing, and anterior clinoid process as a complement to the sphenoid ridge approach in pediatric patients. Patients and Methods: We enrolled 36 patients with suspected neoplastic diseases in different regions. The E-SRA was performed to treat the patients. Patients were included based on the a priori objective of a biopsy or a total gross resection. The surgical time required to complete the approach, associated bleeding, and any complications were documented. Results: Our results demonstrated that the proposed a priori surgical goal, biopsy, or resection were successfully achieved in all cases. In addition, using the E-SRA technique was associated with a shorter operative time, minimal bleeding, and a lower incidence of complications. The most frequently encountered complications were related to dural closure. Conclusions: The extended sphenoid ridge approach represents a safe and effective option for managing intracranial tumors in pediatrics. [ABSTRACT FROM AUTHOR]

Objective: Optic pathway gliomas (OPGs) constitute approximately 3–5% of childhood intracranial tumors. In this study, the authors presented their experience of using the endoscopic endonasal approach to treat patients with OPG located in the chiasma-hypothalamic region and aimed to use the infrachiasmatic corridor in the endoscopic endonasal approach as an alternative to the transcranial approach in the surgical necessity of OPGs. Methods: We retrospectively analyzed the data of ten patients diagnosed with OPG histopathologically among 3757 cases who underwent endoscopic endonasal surgery between August 1997 and March 2021 at Kocaeli University Faculty of Medicine Pituitary Research Center and Department of Neurosurgery. Mean follow-up period 48.5 months. During the postoperative follow-up period, 3 of these 10 patients underwent reoperation due to tumor recurrence. Combined (endoscopic endonasal approach + transcranial approach) approach was applied to 2 patients in the same session. Surgical and clinical outcomes were evaluated in detail. Results: Ten patients with a mean patient age of 20.6 ± 11.4 were included in this study. The most common complaint was visual impairment. After surgery, improvement in visual impairment was observed in five patients. No increase in postoperative visual impairment was observed in any of the patients. Postoperative panhypopituitarism was not observed in any of the patients. STR resection was performed in 5 patients and NTR resection in 5 patients. No additional treatment was required during follow-up in 4 of 5 patients who underwent NTR. A total of 6 patients received postoperative radiotherapy treatment. Conclusions: In gliomas located in the chiasma-hypothalamic region, appropriate patient selection and endoscopic endonasal surgical treatment may contribute to the elimination of symptoms due to the mass effect of the tumor. It may also contribute to keeping the disease under control with targeted adjuvant therapies by clarifying the pathological diagnosis of the lesion. [ABSTRACT FROM AUTHOR]

Objective: Neurofibromatosis (NF) is the most common autosomal dominantly inherited neurocutaneous syndrome. The characteristic features of NF type 1 (NF-1) are café au lait spots, axillary and inguinal freckling, peripheral neurofibromas, optic pathway glioma, and Lisch nodules. The present study aimed to analyze the clinical features of children with NF-1. Materials and Methods: In this study, the children with NF-1 diagnosed and followed-up in our center between 2000 and 2020 were retrospectively evaluated. Demographic and clinical features of patients were defined. Results: The study group consisted of 52 patients. Of those, 25 were boys and 27 were girls. The children's median age at diagnosis was 5.9 years (1-15.8). Café au lait (CAL) spots and axillary/ inguinal freckling were observed in 50 and 24 patients, respectively. Neurofibroma was present in 22 cases. Ten of the cohort had optic gliomas, and 39 of them had cranial hamartomas. Orthopedic complications such as scoliosis, tibial pseudoarthrosis, and osteoporosis were observed in 13 patients. Eleven children had neurocognitive disorders. Conclusions: Early diagnosis is important in neurofibromatosis to prevent the complications of the disease. Also, neurological development and secondary malignancy follow-up should be done carefully in this group of patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the variant spectrum and genotype–phenotype correlations in a Turkish cohort with Neurofibromatosis Type‐1 (NF1). Materials and methods: We retrospectively investigated the clinical and molecular data of 138 NF1 patients from 129 families who had been followed‐up for a median of 3.9 (1.25–18.5) years. Results: NF1 sequencing revealed 73 different intragenic variants, 19 of which were novel. Seven large deletions were detected by multiplex ligation‐dependent probe amplification (MLPA) analyses. The total detection rate of pathogenic NF1 variants was found to be 87.1%. Comparing age groups, cutaneous neurofibromas, freckling, and Lisch nodules were more prevalent in patients older than 12 years (p >.05). Optic glioma detected in 17.3% of the patients and was significantly more common before the age of 6 (p >.001). Other solid tumors developed in 5% of the patients. There was no genotype–phenotype correlation between patients with truncating and nontruncating variants. However, six out of seven patients with large deletions had significant developmental delay, one patient with the c.2970_2972delAAT (p.Met992del) variant had only typical pigmentary features, and another patient with the c.4267A > G (p.Lys1423Glu) variant had CALMs, freckling, neurofibromas, and Noonan‐like phenotype. Conclusions: We described 19 novel variants and seven large deletions in NF1. Applying MLPA assay in NF1 is useful in expanding the molecular diagnosis. Although very limited genotype–phenotype correlation has been reported in NF1, the fact that specific phenotypic findings were observed in our patients with large deletions and two intragenic variants supports the studies published recently. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 is an autosomal dominant disorder which is characterized by multiple café-au-lait spots in the body, intertriginous freckles, Lisch nodules, neurofibroma, optic glioma and bone dysplasia. One of the clinical characteristics of Neurofibromatosis type 1 is the risk of benign and malignant tumor development. Optic gliomas, a type of astrocytoma, are the most common central nervous system complication in children with Neurofibromatosis type 1 and are seen in 10-15% of cases. In this case report, a patient with an optic glioma and a mutation that was not previously identified in the NF1 gene is presented in the light of the literature. Identification of new mutations that cause Neurofibromatosis type 1 disease and reporting of clinical findings caused by the mutations will allow a large proportion of genotypephenotype correlation. Early diagnosis has a great importance in terms of followup of patients for malignancies that may develop in the future. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 is a relatively common genetic disease, with a prevalence ranging between 1/3000 and 1/6000 people worldwide. The disease affects multiple systems with cutaneous, neurologic, and orthopedic as major manifestations which lead to significant morbidity or mortality. Indeed, NF1 patients are at an increased risk of malignancy and have a life expectancy about 10-15 years shorter than the general population. The mainstay of management of NF1 is a patient-centered longitudinal care with age-specific monitoring of clinical manifestations, aiming at the early recognition and symptomatic treatment of complications as they occur. Protocole national de diagnostic et de soins (PNDS) are mandatory French clinical practice guidelines for rare diseases required by the French national plan for rare diseases. Their purpose is to provide health care professionals with guidance regarding the optimal diagnostic and therapeutic management of patients affected with a rare disease; and thus, harmonizing their management nationwide. PNDS are usually developed through a critical literature review and a multidisciplinary expert consensus. The purpose of this article is to present the French guidelines on NF1, making them even more available to the international medical community. We further dwelled on the emerging new evidence that might have therapeutic potential or a strong impact on NF1 management in the coming feature. Given the complexity of the disease, the management of children and adults with NF1 entails the full complement healthcare providers and communication among the various specialties. [ABSTRACT FROM AUTHOR]

Objective: Optic gliomas are histologically benign and well differentiated pilocytic astrocytomas. The histopathologic features of the tumor are important prognostic markers that affect survival rates in association with location, the age of the patient, and neurofibromatosis type-1. Chemotherapy is the most important choice in the treatment and the clinicians' goal is to stay as far away from radiotherapy as possible. The combination of vincristine and carboplatin, which is a safe and long-lasting safe treatment plan that sets the stage for radiotherapy and surgeon avoidance, is one of the first choice standard treatment approaches. However, in these treatments, refractory disease, imatinib mesylate, a multi-tyrosine kinase inhibitor with a low rate of systemic side effects can be added as an important option. It can be used safely in pediatric patients. Because of small number of studies reported in this area, we wanted to share our good results regarding the use of imatinib mesylate with clinicians. Material and Methods: A total of 16 patients with optic glioma who were diagnosed between 2007-2017 at our oncology clinic were included in the study. Results: When clinically and radiologically progressive disease was present after two cycles of the vincristine carboplatin combination, imatinib (270 mg/m2 oral) treatment was added for 1-2 years until stable disease or regression findings were observed. The median follow-up period of the patients was 7 (5-10) years. There was a complete response in four patients and stable disease findings in two patients. There was no imatinib-related side effect in our patients. Conclusion: Imatinib acts mainly by inhibiting the expression of PDGFR-a and P from tumor capillary endothelia. We believe that the inclusion of smart target molecules will reduce the need for radiotherapy, which is associated with late side effects in progressive disease. Many molecular targeting agents that may be implemented in the future may enter the treatment of refractory optic gliomas and children can be protected from complications arising from surgery and radiotherapy in this manner. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a autosomal-dominant multi-systemic disorder derives from a mutation in the 17q11.2 gene (1). The incidence is 1 in 2500-3500 live births and the prevalence is 1 in 4000-5000. The characteristic features of this disease are café-au-lait spots, freckling in intertriginous regions and Lisch nodules. Although NF1 is considered as a tumor predisposing sydrome over cenral and peripheral nervous system tumors it presents wide nonneoplastic conditions including pigmental abnormalities (are café-au-lait spots, freckling in intertriginous regions and Lisch nodules), skeleton abnormalities and neurobehavioral abnormalities ( learning disorder, attention deficit disorder, hyperactivity disorder). The initial definition of endocrine disorders, the complication of NF1, goes back to the 1970s. We discussed the prececious puberty detected in the monitoring of NF1 male patient, who is 8 and a half years old, with optic pathway glioma in this paper. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder, in which affected individuals develop tumors of the nervous system. Children with NF1 are particularly prone to brain tumors (gliomas) involving the optic pathway that can result in impaired vision. Since tumor formation and expansion requires a cooperative tumor microenvironment, it is important to identify the cellular and acellular components associated with glioma development and growth. In this study, we used 3-D matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to measure the distributions of multiple molecular species throughout optic nerve tissue in mice with and without glioma, and to explore their spatial relationships within the 3-D volume of the optic nerve and chiasm. 3-D IMS studies often involve extensive workflows due to the high volume of sections required to generate high quality 3-D images. Herein, we present a workflow for 3-D data acquisition and volume reconstruction using mouse optic nerve tissue. The resulting 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions. Biological significance The current work addresses a number of challenges in 3-D MALDI IMS, driven by the small size of the mouse optic nerve and the need to maintain consistency across multiple 2-D IMS experiments. The 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions, which could then be targeted for identification and related back to the biology observed in gliomas of the optic nerve. [ABSTRACT FROM AUTHOR]

Purpose: Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital neurocutaneous disorder. It was described by Haberland in 1970 and is also called Haberland syndrome. It is characterized by unilateral skin lesions such as lipomas, connective tissue nevi, and alopecia with ipsilateral ophthalmological and cerebral malformations with or without psychomotor and mental retardation and early-onset seizure. Methods: We present three pediatric cases (two boys, one girl) with ECCL. All the patients' sociodemographic, clinical, and neuroradiological data was collected. Results: We describe two male (5 and 1.3 years old) and one female (15 years old) cases. All patients have unilateral left-sided alopecia with ipsilateral ocular lesion and the cerebral lesion. All patients were born at term; their past history and family histories were unremarkable. Their electroencephalograms showed hemispheric asymmetry. All of the cases had right-sided mild to moderate hemiparesis. In addition, our second case is having optic glioma and this case is the fifth case with glioma associated with ECCL. Conclusions: We describe three additional cases with ECCL which is an extremely rare neurocutaneous syndrome. Also, case 2 has optic glioma and according to the literature this is the fifth case of low-grade gliomas with ECCL. We suggest that patients who have ocular lesion and ipsilateral skin lesion must be examined for ECCL, and the patients must be followed up with cerebral MRI once a year for low-grade gliomas. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder with an extremely variable phenotype. In childhood NF1 can be associated with optic glioma and central precocious puberty; the latter is more common when the optic chiasm is affected. The mutational spectrum of the NF1 gene is wide and complex; R681X is a rare severe mutation of the NF1 gene known to cause truncation of neurofibromin, with only ten reported cases in the literature so far. Case presentation: We describe a girl with NF1 associated with early central precocious puberty appearing at 2.5 years of age and optic glioma affecting the optic chiasm as seen on magnetic resonance imaging (MRI). Genetic analysis confirmed the presence of R681X. Therapy with a gonadotropin-releasing hormone agonist was instituted with good response to therapy. The lesions on MRI were stable and no significant vision impairment was present during the 6 years of follow-up. Conclusion: Of the ten reported cases of NF1 due to R681X, one has presented with optic glioma and none with precocious puberty. Thus, to our knowledge, this is the first reported case of this mutation presenting with precocious puberty. We believe that this is a contribution to the few reports on the phenotype of this mutation and to the future elucidation of genotype-phenotype correlations of this disease. [ABSTRACT FROM AUTHOR]

Orbital tumors constitute a group of diverse lesions with a low incidence in the population. Tumors affecting the eye and ocular adnexa may also secondarily invade the orbit. Lack of accumulation of a sufficient number of cases with a specific diagnosis at various orbital centers, the paucity of prospective randomized studies, animal model studies, tissue bank, and genetic studies led to the development of various myths regarding the diagnosis and treatment of orbital lesions in the past. These myths continue to influence the diagnosis and treatment of orbital lesions by orbital specialists. This manuscript discusses some of the more common myths through case summaries and a review of the literature. Detailed genotypic analysis and genetic classification will provide further insight into the pathogenesis of many orbital diseases in the future. This will enable targeted treatments even for diseases with the same histopathologic diagnosis. Phenotypic variability within the same disease will be addressed using targeted treatments. [ABSTRACT FROM AUTHOR]

Purpose: Optic pathway cavernous malformations (CMs) are extremely rare, accounting for less than 1 % of all intracranial CMs. We report a case of optic pathway CM mimicking optic glioma because the initial magnetic resonance (MR) images did not disclose hemorrhagic findings such as popcorn-like lesion or hemosiderin ring. Methods: A 20-year-old woman presented with subacute left visual acuity loss and visual field defect and was referred to our hospital. Initial MR imaging findings were suggestive of optic glioma. Second MR imaging demonstrated hemorrhagic findings, but the hemorrhage was considered to be intratumoral hemorrhage from left optic pilocytic astrocytoma. She underwent radiochemotherapy and intravenous administration of corticosteroids but her symptoms deteriorated. Third and fourth MR imaging revealed enlargement of the hematoma. Therefore, the radiation therapy was interrupted at a delivered dose of 16.2 Gy, and craniotomy was performed to preserve residual right visual field. The lesion was totally removed and the histological diagnosis was CM. Her right visual field was preserved, but not improved. Results: The present case and previous cases suggest that optic pathway CMs sometimes do not initially manifest with signs of hemorrhage, so CMs should be included in the differential diagnosis of optic pathway lesions. Conclusions: Histological confirmation with preparation for total resection should be considered for rapidly progressive cases even if the neuroimaging findings are compatible with optic glioma. [ABSTRACT FROM AUTHOR]

Children with the neurofibromatosis type 1 (NF1) inherited tumor predisposition syndrome are at risk for the development of brain tumors. In addition, children with neurofibromatosis type 1 often exhibit low tone (hypotonia). In this study, the authors explored the hypothesis that hypotonia could be a clinical indicator of glioma in children with neurofibromatosis type 1. A total of 56 children between 1 and 7 years of age with a confirmed diagnosis of neurofibromatosis type 1 were evaluated. Brain magnetic resonance imaging (MRI) was available for 19 of these children. Chi-square analysis demonstrated a statistically significant correlation between hypotonia and glioma in children with neurofibromatosis type 1 (90% sensitivity and 78% specificity). These results suggest that hypotonia might be a clinically useful indicator of brain tumor in this at-risk population. [ABSTRACT FROM PUBLISHER]

Background: Optic nerve tortuosity is often reported in children with neurofibromatosis type 1 (NF1). Objective: To employ quantitative and subjective criteria to assess optic nerve tortuosity in individuals with NF1. Materials and methods: A retrospective study over a period of 8 years was performed on children with NF1, with and without optic pathway glioma, compared with children without NF1. A tortuosity index was computed for the optic nerve in each child using a high-resolution 3-D T1-weighted magnetization-prepared rapid gradient-echo sequence, which was averaged and compared across groups. Results: The tortuosity index for subjects with NF1, regardless of an optic pathway glioma, was greater than those without NF1. There was no difference in the tortuosity index between NF1 subjects with optic pathway glioma and NF1 subjects without optic pathway glioma. There was also no correlation between subjective measures of tortuosity and the quantitative scoring (tortuosity index) or between the degree of tortuosity and subject age or gender. Conclusion: Individuals with NF1 have increased optic nerve tortuosity relative to unaffected individuals. Quantitative tortuosity index is a superior measure to subjective assessment in the evaluation of optic nerve tortuosity in children with NF1. [ABSTRACT FROM AUTHOR]

Introduction: Optic gliomas are the most common tumors in the optic pathways during childhood. Among them, about 10 % are located within intra-orbital cavity. However, the optimal management for intra-orbital optic nerve gliomas remains controversial. An 11-year-old male complained about progressive decline of vision in his right eye. Brain MRI revealed a fusiform enlargement of right optic nerve within intra-orbital cavity. Materials and methods: A presumptive diagnosis of optic nerve glioma was made. Therefore, we performed fractionated stereotactic radiotherapy (FSRT) using Novalis. Discussion: Five years after FSRT treatment, follow-up MRI revealed size reduction of tumor and visual acuity improvement without radiation-related complications. [ABSTRACT FROM AUTHOR]

A 5-year-old female presented to the emergency department with a 24-hour history of nausea, vomiting and mental status changes. Imaging demonstrated hemorrhage from a suprasellar mass consistent with an optic nerve glioma. The patient was taken to surgery for an open biopsy and hematoma evacuation. Pathology revealed a grade 3 fibrillary astrocytoma. She was subsequently treated with carboplatin and vincristine and is now 2 years out without evidence of recurrence. Apoplexy is a rare presentation for an optic pathway glioma. To the authors' knowledge, this is the first reported case in the pediatric population. Clinical presentation appears similar to the symptoms observed in pituitary apoplexy. Timely surgery should be directed at obtaining diagnostic tissue, prevention of long-term nervous system damage and evacuation of the hematoma where feasible. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher's attention, in view of possible clinical use in Alzheimer's disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases. [ABSTRACT FROM AUTHOR]

Objects: We aim to evaluate the characteristics of pediatric patients with neurofibromatosis type 1 (NF1) who developed soft tissue sarcomas (STSs) and central nervous system (CNS) tumors that have been followed up in our center. Materials and methods: Medical records of children with NF1 were retrospectively analyzed. Results: There were 78 patients who met at least two diagnostic criteria for NF1. The median age of patients was 10 years (0.5-18), and M/F ratio was 1.3. The prevalance of the optic glioma was 11.5% ( n = 9), and one patient with optic glioma also had cystic astrocytoma, one patient had brain stem tumor, and one patient had a CNS tumor (without histopathologic diagnosis). Seven of nine children were ≥7 years old at the time of the diagnosis of optic glioma. Visual impairment developed in four patients, and two of them were treated with radiotherapy solely on the basis of evidence of clinical and radiological progression of the tumors. Four patients developed STSs. Two of them had malignant peripheral nerve sheath tumors (MPNST), and the remaining two had bladder rhabdomyosarcoma. Three of the four patients with STSs died with progressive disease. Conclusion: The clinical course of malignancy in NF1 is often different from that of similar tumor types in the general population. Careful follow-up in patients with NF1 is required to enable the early diagnosis of malignancies, and the developments of new targeted therapies are needed for improvement of the outcome for patients of this group, especially with MPNST. [ABSTRACT FROM AUTHOR]

Converging evidence from the analysis of human brain tumors and genetically engineered mice has revealed that the mammalian target of rapamycin (mTOR) pathway is a central regulator of glial and glioma cell growth. In this regard, mutational inactivation of neurofibromatosis-1 (NFl), tuberous sclerosis complex (TSC), and PTEN genes is associated with glioma formation, such that pharmacologic inhibition of mTOR signaling results in attenuated tumor growth. This shared dependence on mTOR suggests that PTEN and NFl (neurofibromin) glial growth regulation requires TSC/Rheb (Ras homolog enriched in brain) control of mTOR function. In this report, we use a combination of genetic silencing in vitro and conditional mouse transgenesis approaches in vivo to demonstrate that neurofibromin regulates astrocyte cell growth and glioma formation in a TSC/Rheb-independent fashion. First, we show that Nfl or Pten inactivation, but not Tscl loss or Rheb overexpression, increases astrocyte cell growth in vitro. Second, Nfl-deficient increased mTOR signaling and astrocyte hyperproliferation is unaffected by Rheb shRNA silencing. Third, conditional Tscl inactivation or Rheb overexpression in glial progenitors of Nf1+/- mice does not lead to glioma formation. Collectively, these findings establish TSC/Rheb-independent mechanisms for mTOR-dependent glial cell growth control and gliomagenesis relevant to the design of therapies for individuals with glioma. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to investigate the progression of changes in retinal ganglion cells and optic nerve glia in neurofibromatosis-1 (NF1) genetically-engineered mice with optic glioma. Optic glioma tumors were generated in Nf1+/− mice lacking Nf1 expression in GFAP+ cells (astrocytes). Standard immunohistochemistry methods were employed to identify astrocytes (GFAP, S100β), proliferating progenitor cells (sox2, nestin), microglia (Iba1), endothelial cells (CD31) and retinal ganglion cell (RGC) axons (Neurofilament 68k) in Nf1+/−, Nf1 GFAPCKO (wild-type mice with Nf1 loss in glial cells), and Nf1+/−GFAPCKO (Nf1+/− mice with Nf1 loss in glial cells) mice. Ultrastructural changes in the optic chiasm and nerve were assessed by electron microscopy (EM). RGC were counted in whole retina preparations using high-resolution, mosaic confocal microscopy following their delineation by retrograde FluoroGold labeling. We found that only Nf1+/− GFAPCKO mice exhibited gross pre-chiasmatic optic nerve and chiasm enlargements containing aggregated GFAP+/nestin+ and S100β+/sox2+ cells (neoplastic glia) as well as increased numbers of blood vessels and microglia. Optic gliomas in Nf1+/−GFAPCKO mice contained axon fiber irregularities and multilamellar bodies of degenerated myelin. EM and EM tomographic analyses showed increased glial disorganization, disoriented axonal projections, profiles of degenerating myelin and structural alterations at nodes of Ranvier. Lastly, we found reduced RGC numbers in Nf1+/− GFAPCKO mice, supporting a model in which the combination of optic nerve Nf1 heterozygosity and glial cell Nf1 loss results in disrupted axonal-glial relationships, subsequently culminating in the degeneration of optic nerve axons and loss of their parent RGC neurons. [ABSTRACT FROM AUTHOR]

There is little consensus regarding optimal surveillance of optic pathway glioma (OPG) and plexiform neurofibroma (PNF) in childhood neurofibromatosis type 1 (NF1). 18F-2-Fluoro-2-deoxy- D-glucose (FDG) positron emission tomography and computed tomography (PET/CT) is employed in the surveillance of adult PNFs; but its utility has neither been specifically studied in children with PNFs nor in children with OPG. Review of PET/CT studies was performed in NF1 children with OPG or PNF. FDG-avidity of tumours was semi-quantitatively analysed and graded by calculating the maximum standardised uptake value (SUVmax) [grade 1: <3 (low), grade 2: >3–<4 (intermediate), grade 3: >4 (intense)]. Eighteen children (ten girls; median age: 8.5–years) had PET/CT. Nineteen OPGs were imaged. The SUVmax could be measured in 16. Ten were grade 1 and three each were grade 2 and grade 3. FDG-avidity reduced from grade 3 to grade 1 in two symptomatic OPGs following chemotherapy and this was associated with clinical improvement. PET/CT diagnosed symptomatic OPGs with a sensitivity of 0.625 [95% confidence interval (CI): 0.259–0.897] and specificity of 0.875 (95% CI: 0.466–0.993). Sixteen PNFs were imaged. Twelve were grade 1 and two each were grade 2 and grade 3. The two grade 3 PNFs were confirmed malignant peripheral nerve sheath tumours. PET/CT diagnosed malignant transformation with a sensitivity of 1.0 (95% CI: 0.197–1.0) and specificity of 0.857 (95% CI: 0.561–0.974). PET/CT may contribute useful information to the surveillance of OPG in childhood NF1—particularly to identify progressive, symptomatic tumours. As in adults, PET/CT is useful for the detection of malignant transformation in PNFs in children with NF1. [ABSTRACT FROM AUTHOR]

We report a rare case of atypical teratoid/rhabdoid tumor that presented with imaging findings similar to those of optic pathway glioma. The diagnosis of atypical teratoid/rhabdoid tumor was determined following surgical resection of the tumor by collective histologic and immunohistochemical staining, and cytogenetic analysis. We describe the clinical presentation, neuroimaging findings and pathology, and compare them to those of optic gliomas. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders and the major constituent of a family of diseases with widespread manifestations (including skin, viscera, nervous system and eyes) clinically known as "phakomatoses". Patients with NF1, carry a high risk of tumor formation. The most common central nervous tumor in NF1 is the optic pathway glioma (OPG). 0.6% of all childhood malignancies are associated with NF1. In patients with NF1 while the risk of developing OPG is 1000 times more than the normal population, the risk of developing brain and spinal tumors are 40, soft tissue sarcomas 50, juvenile myelomonocytic leukemia 200, acute lymphoblastic leukemia five times more than the normal population. General practitioners and pediatricians should be aware of signs and symptoms of neurofibromatosis. They should also know that the risk of tumor formation is increased in these patients, and early diagnosis is key point for the success of treatment. [ABSTRACT FROM AUTHOR]

Neurofibromatosis 1 is a multisystem disorder that primarily involves the skin and nervous system. Its population prevalence is 1 in 3500. The condition usually is recognized in early childhood, when cutaneous manifestations are apparent. Although neurofibromatosis 1 is associated with marked clinical variability, most affected children do well from the standpoint of their growth and development. Some features of neurofibromatosis 1 are present at birth, and others are age-related abnormalities of tissue proliferation, which necessitate periodic monitoring to address ongoing health and developmental needs and to minimize the risk of serious medical complications. This clinical report provides a review of the clinical criteria needed to establish a diagnosis, the inheritance pattern of neurofibromatosis 1, its major clinical and developmental manifestations, and guidelines for monitoring and providing intervention to maximize the growth, development, and health of an affected child. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effectiveness of Novalis radiosurgery (RS) in children with optic gliomas. Methods: Four pediatric patients (1 male and 3 female) were treated for optic gliomas with Novalis RS in our institution between February 2002 and July 2002. Their mean age was 12 (range 5–16) years at presentation for Novalis RS. The mean target dose was 44 (range 41–45) Gy, with a mean fractionation dose of 1.58 (range 1.5–1.65) Gy. Follow-up included magnetic resonance imaging and ophthalmologic and endocrine examinations. Results: The mean follow-up period was 54 (range 50–58) months. During the follow-up period, all patients were alive. Local control of the tumor was obtained in all patients. None of the patients showed clinically relevant morbidity, especially endocrine dysfunction. Conclusions: Novalis RS may be an excellent treatment method for optic gliomas in children. However, long-term follow-up is required for further evaluation of efficacy and potential side effects. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Optic nerve glioma is the most common primary neoplasm of the optic nerve in childhood. It can extend intracranially along the optic pathway (optic pathway glioma). The lesion tends to present with decreased visual acuity in the affected eye, but can cause additional symptoms when it is large. Local involvement within the orbit can be characterized using CT, but MRI is superior in showing the intracranial extent of the lesion. Intracranial calcification in optic pathway glioma is rare. We present a rare case of optic pathway glioma with calcification in the intracranial component. Also, we describe MR spectroscopy (MRS) findings in this case. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effectiveness and toxicity of fractionated stereotactically guided radiotherapy (FSRT) in the management of optic glioma. Methods and Materials: Fifteen patients with optic pathway gliomas were treated with FSRT at our institution between 1990 and 2003. A median target dose of 52.2 Gy (range, 45.2–57.6 Gy) was applied using a median fractionation of 5 fractions of 1.8 Gy weekly using a linear accelerator. Results: The median follow-up time was 97 months (range, 8–151 months). Of the 15 patients, 1 died of tumor progression during the follow-up period. The progression-free survival rate at 3 and 5 years was 92% and 72%, respectively. The median overall survival after FSRT was 90 months (range, 8–151 months). The 5-year survival rate after FSRT was 90%. We did not observe secondary malignancies. Conclusion: Fractionated stereotactic radiotherapy was safe and well tolerated in all patients. The good tumor control and the potential of sparing normal brain tissue, especially the pituitary gland in lesions involving the optic chiasm, permit effective treatment of patients with optic nerve gliomas. Longer follow-up is needed to assess the incidence of late effects fully. [Copyright &y& Elsevier]

Neurofibromatosis (NF) is the most common of the phakomatoses, with a prevalence of 1 in 3-4,000. Many organ systems can be affected. In addition to multiple peripheral neurofibromas, NF I predisposed to CNS tumors including optic glioma, astrocytoma and plexiform neurofibroma. The purpose of this pictorial review is to illustrate characteristic brain MR imaging lesions in children with NF I and to give some recommendations about diagnostic imaging procedures in children suffering from NF I. Typical findings in brain MRI are hyperintense lesion on T2-weighted images, so-called unknown bright objects, which may be useful as an additional imaging criterion for NF I. Contrast administration is necessary in MR studies to maximize tumor detection and characterization, to add confidence to the diagnosis of benign probable myelin vacuolization, and to document stability of neoplasm on follow-up examinations. We recommend to perform serial MR imaging in children every 12 months. The frequency of follow-up in children with known brain tumors will vary with the tumor grade, biological activity and treatment. [ABSTRACT FROM AUTHOR]

A 12-year-old girl with neurofibromatosis type 1 presented with headache, visual acuity and visual field disturbance. Computed tomography and magnetic resonance imaging revealed an enhanced solid mass involving her right optic nerve and optic chiasm, and a cystic lesion in the pineal region that had resulted in obstructive hydrocephalus. An open biopsy of the right optic nerve tumour was performed, and it was histologically identified as a pilocytic astrocytoma. Local irradiation of 50 Gy to the optic pathway tumour was performed, and the tumour has remained stable for more than 29 months. On the contrary, the pineal cystic mass that was also histologically identified as a pilocytic astrocytoma showed marked enlargement within 5 months after a subtotal resection. Chemotherapy with cisplatin and vincristine was performed after a second surgery, and the pineal tumour has not re-grown in 18 months. To our knowledge, this is the first case report to describe synchronous optic and pineal pilocytic astrocytomas associated with neurofibromatosis type 1. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To evaluate a fast technique of visual evoked potentials (VEPs) recording, in response to steady-state luminance stimuli (SS-LVEPs), for functional assessment and follow-up of childhood optic gliomas (OGs).Methods: Eighteen OG patients (age range: 3.5–18 years), with different degrees of optic pathway damage severity, were examined. Sixteen age-matched normal subjects served as controls. Ten of the 18 OG patients were re-tested 1–3 months after the first examination. SS-LVEPs were elicited by a sinusoidally-modulated flickering (8 Hz) uniform field, generated by a light emitting diode (LED)-array and presented monocularly in a mini-ganzfeld. Amplitude and phase of the Fourier-analyzed response fundamental (1F) and second harmonic (2F) were measured. The full VEP protocol had a median duration of 6 min (range: 4–12).Results: When compared to normal control values, median 1F and 2F SS-LVEP amplitudes of OG patients were reduced (P<0.01), with a borderline increase in 2F phase lag (P<0.05). In 11 OG patients with asymmetric optic pathway damage in between-eye comparisons, median 1F amplitude losses were greater (P<0.01) in fellow eyes with more severe damage. No significant interocular difference was observed in control subjects. Median test-retest changes of 1F and 2F component were <20% and 30° for amplitude and phase, respectively. In individual OG patients, 1F and 2F amplitudes were positively correlated (P<0.01) with visual acuity. 1F amplitude losses were correlated (P=0.01) with the severity of optic disc atrophy. Considering both 1F and 2F abnormalities, diagnostic sensitivity of SS-LVEP in detecting OG-induced optic pathways damage was 83.3%.Conclusions: The present findings support the use of this technique, as an alternative to pattern VEPs, for functional assessment and follow-up of OG in uncooperative children. [Copyright &y& Elsevier]

In a control group of 12 normal children (ages ranging from 9 months to 3 years; mean=1.6 years) the mean apparent diffusion coefficient (ADC) value of the normal white matter, obtained from automatically generated ADC maps, was 0.84±0.14×10−3 mm2/s. A patient with neurofibromatosis type 1 with bilateral optic gliomas, and extensive optic pathway involvement was evaluated by diffusion MRI. Multiple measurements of ADC values throughout the involved optic radiations revealed a higher mean value: 1.16±0.06×10−3 mm2/s than that of the normal white matter, suggesting relatively high molecular motion in these regions, probably representing myelin vacuolization. ADC evaluation of a thalamic hamartoma revealed a lower value (=1.06×10−3 mm2/s) than this. The mean ADC value obtained from multiple measurements of the enlarged optic chiasm, and intraorbital portions of the nerve was similar (=0.81±0.09×10−3 mm2/s) to that of the normal cerebral white matter of the control cases. It appears that diffusion imaging can be useful in evaluation of optic pathway involvement in NF1, and might contribute to differentiating optic gliomas from hamartomas, and myelin vacuolization, however, further studies will be required for assessing the role of diffusion imaging in such lesions. [Copyright &y& Elsevier]

Optic glioma (OPG) accounts for 4–8% of all brain tumors in children. En-block removal of intraorbital tumor is recommended in cases with disfiguring exophthalmos and impaired vision. Surgical resection of intraorbital optic nerve (ON) poses the risks of permanent ptosis and globe atrophy. We present here the case of a 4-year-old boy with exophthalmos and near blindness due to an intraorbital OPG. Despite chemotherapy he showed progressive exophthalmos and vision loss. Bony orbital decompression with ON transection temporally reduced his exophthalmos. OPG resection was required later for recurrence of his exophthalmos secondary to tumor progression. Post operatively, he had preserved oculomotor nerve functions but developed globe ischemia. Unusually, his ischemic globe caused him to have pain and severe photophobia, which later lead to enucleation. Photophobia has been reported in blind patients. Animal models and MRI functional imaging showed activation of trigeminal pathway during photophobia in completely transected ON. However, the exact neuro-ophthalmology pathway requires further study. Conclusion This is the first described case of photophobia after excision of OPG with ON denervation. Photophobia can be a serious side effect that significantly lowers the patient's quality of life. [ABSTRACT FROM AUTHOR]

We report a case of optic glioma with bilateral optic atrophy. A 3-year-old girl presented with vomiting and left hemiparesis. She had hypothalamic dysfunction, right ptosis, right monocular nystagmus, left facial palsy, left hemiparesis, and left pes adductus. Neuroimaging studies showed obstructive hydrocephalus with a large suprasellar calcified tumor with a ring-like enhancement mimicking craniopharyngioma. Visual-evoked potentials showed delayed latency of N[sub 75] in the right occipital lead. The tumor, a pilocytic astrocytoma in the right optic tract and chiasma, was partially removed via a right fronto-temporal craniotomy. The right optic nerve had shrunk to half the normal diameter and became twisted downwardly. Intracranial pressure (ICP) increased to 40 cm H[sub 2] O. The fundus had bilateral optic atrophy without disc swelling. To our knowledge, this is the first report of a lamina/dot sign of the optic disc in a small child with a brain tumor and a normal neuroretinal fiber layer. These ocular findings may result from possible interruption of the axonal flow caused by the tumor and not increased ICP.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A major concern during the early postoperative period after surgical resection of optic chiasmatic gliomas is the derangement of sodium and water metabolism which may add to the morbidity of the procedure. The purpose of this study was to characterize the abnormalities of water and sodium metabolism in children with optic chiasmatic gliomas treated surgically at British Columbia’s Children’s Hospital and to identify therapeutic modalities which might prevent or ameliorate the development of these complications. A retrospective chart review of children with optic/chiasmatic gliomas undergoing operations on the tumor was performed and the pre- and postoperative radiographs reviewed by an independent neuroradiologist. There were 11 patients who underwent 13 operations for either resection (n = 9) or biopsy (n = 4) of their optic chiasm tumor. The extent of resection in patients undergoing more than simple biopsy ranged from 83 to 99%, and all patients with resection had exophytic tumor extending into the hypothalamus. Postoperative syndrome of inappropriate antidiuretic hormone secretion (SIADH) and/or diabetes insipidus occurred after 8 of the 9 tumor resections and was associated with significant morbidity. No disturbance of water metabolism occurred after biopsy only. In patients with SIADH, the urinary sodium level rose markedly 6–12 h prior to the development of hyponatremia, and it was concluded that this was a valuable predictor of impending hyponatremia. Replacement of urine output was noted to be the most reliable way to avoid rapid fluctuations in serum sodium and to avoid the morbidity of diabetes insipidus or SIADH and is recommended in the postsurgical patients who cannot regulate fluid intake. [ABSTRACT FROM AUTHOR]

Non-coding RNAs (ncRNAs) are known to regulate gene expression at the transcriptional and post-transcriptional levels, chromatin remodeling, and signal transduction. The identification of different species of ncRNAs, microRNAs (miRNAs), circular RNAs (circRNAs), and long ncRNAs (lncRNAs)—and in some cases, their combined regulatory function on specific target genes—may help to elucidate their role in biological processes. NcRNAs' deregulation has an impact on the impairment of physiological programs, driving cells in cancer development. We here carried out a review of literature concerning the implication of ncRNAs on tumor development in neurofibromatosis type 1 (NF1), an inherited tumor predisposition syndrome. A number of miRNAs and a lncRNA has been implicated in NF1-associated tumors, such as malignant peripheral nerve sheath tumors (MPNSTs) and astrocytoma, as well as in the pathognomonic neurofibromas. Some authors reported that the lncRNA ANRIL was deregulated in the blood of NF1 patients with plexiform neurofibromas (PNFs), even if its role should be further elucidated. We here provided original data concerning the association of a specific genotype about ANRIL rs2151280 with the presence of optic gliomas and a mild expression of the NF1 phenotype. We also detected the LOH of ANRIL in different tumors from NF1 patients, supporting the involvement of ANRIL in some NF1-associated tumors. Our results suggest that ANRIL rs2151280 may be a potential diagnostic and prognostic marker, addressing early diagnosis of optic glioma and predicting the phenotype severity in NF1 patients. [ABSTRACT FROM AUTHOR]