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1.  Optic Nerve Tortuosity in Individuals with Neurofibromatosis Type 1 
Pediatric radiology  2013;43(10):1336-1343.
Optic nerve tortuosity is often reported in children with neurofibromatosis type 1 (NF1). We describe quantitative and subjective criteria to determine the degree of optic nerve tortuosity in individuals with NF1.
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 to children without NF1. A tortuosity index was computed for the optic nerve in each subject using a high resolution 3D T1-weighted magnetization-prepared rapid gradient echo sequence, which was averaged and compared across groups.
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.
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.
PMCID: PMC3904184  PMID: 23636538
NF1; optic glioma; MRI; brain tumor; cancer predisposition syndrome
2.  Acquired bilateral myelinated retinal nerve fibers after unilateral optic nerve sheath fenestration in a child with idiopathic intracranial hypertension 
To report the unusual development of bilateral myelinated retinal nerve fibers (MRNF) adjacent to the optic nerve in a child after treatment of idiopathic intracranial hypertension (IIH) with unilateral optic nerve sheath fenestration (ONSF) and to discuss the etiology of acquired MRNF.
The patient’s clinical history, including visual acuity, refractive error, ocular alignment, fundus examination, and optic nerve photographs, was retrospectively reviewed. A literature review was performed for acquired MRNF in children using PubMed. The results of the demographic and clinical findings of our patient were compared with those of previously reported cases.
The child developed bilateral MRNF adjacent to the optic nerve 5 months after unilateral ONSF. In reviewing the literature, 8 of 10 cases of acquired MRNF in children had prior abnormalities of the optic nerve, 4 of 10 had associated bilateral optic nerve head drusen, 3 of 10 had associated optic nerve glioma, and 3 of 10 had a history of significant increased intracranial pressure requiring surgical intervention.
While the etiology of acquired MRNF is uncertain, this case plus a review of the literature suggest that it may be related to changes in the lamina cribosa combined with possible optic nerve injury caused by optic nerve head drusen, optic nerve glioma, or elevated intracranial pressure, and that it can occur months to years after intervention.
PMCID: PMC3535484  PMID: 23237749
3.  Atypical clinical presentation and long-term survival in a patient with optic nerve medulloepithelioma: a case report 
Medulloepithelioma is a rare congenital tumor of the primitive medullary neuroepithelium. A significant proportion of patients with medulloepithelioma arising from the optic nerve die from intracranial spread or cerebral metastasis. Because it has no known distinct clinical features and because of its low frequency, this tumor presents within the first two to six years of life and is usually misdiagnosed clinically as a different type of optic nerve tumor. Here, we describe a new and atypical case of medulloepithelioma of the optic nerve in a 12-year-old boy. To the best of our knowledge, he is the oldest reported patient to present with this disease and, now as an adult, has the longest documented period of disease-free survival.
Case presentation
A 12-year-old Caucasian boy with headache and unilateral amaurosis was referred for a presumed optic nerve glioma to our hospital. A computed tomography scan showed optic nerve enlargement, and fundoscopy showed a whitish mass at the optic disc. Our patient had been followed at his local hospital for four years for an 'optic disc cyst' with no change or progression. He experienced mild progressive visual impairment during that period. He was admitted for resection, and a histopathological analysis revealed a medulloepithelioma of the optic nerve. Supplemental orbital radiotherapy was performed. He remained disease-free for 25 years.
Medulloepithelioma of the optic nerve can clinically mimic more common pediatric tumors, such as optic glioma, meningioma, or retinoblastoma. Thus, medulloepithelioma should be included in the differential diagnoses of pediatric optic nerve lesions. Fundoscopy in these patients may provide relevant information for diagnosis. Anterior optic nerve medulloepitheliomas may behave differently from and have a better prognosis than medulloepitheliomas that have a more posterior location. Our case report illustrates that long-term survival can be achieved in patients with this malignant tumor.
PMCID: PMC3359171  PMID: 22571440
4.  Optic glioma of childhood: clinical, histopathological, and histochemical observations. 
This report documents the long-term clinical and histopathological behaviour of eight intraorbital and 16 intracranial optic nerve gliomas and relates the therapeutic data to the prognosis for both visual acuity and survival. The mean age at onset of symptoms was 8.6 years and at the diagnosis 10.9 years. It is generally held that proptosis is mild in intraorbital glioma, but we encountered marked proptosis ranging from 7 to 12 mm in six of the eight intraorbital gliomas, which contained abundant Alcian-blue-positive mucoid material. Of the patients with intracranial optic nerve gliomas 37.5% survived for a mean of eight years after treatment with radiotherapy or surgery combined with radiotherapy. At follow-up ranging from five months to 11 years only one of the six patients with intracranial gliomas had full visual acuity. Our observations emphasise that, although optic nerve gliomas are benign hamartomas, the prognosis for visual acuity and survival is unfavourable in cases which are diagnosed and treated late. Histopathological and histochemical observations suggest that increase in the amount of mucoid material may contribute to rapid enlargement of intraorbital and intracranial optic gliomas.
PMCID: PMC1041895  PMID: 2818994
5.  NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma 
Oncogene  2013;33(3):289-299.
Low-grade glial neoplasms (astrocytomas) represent one of the most common brain tumors in the pediatric population. These tumors frequently form in the optic pathway (optic pathway gliomas; OPGs), especially in children with the Neurofibromatosis Type 1 (NF1) inherited tumor predisposition syndrome. To model these tumors in mice, we have previously developed several Nf1 genetically-engineered mouse (GEM) strains that form optic gliomas. However, there are three distinct macroglial cell populations in the optic nerve (astrocytes, NG2+ cells and oligodendrocytes). The presence of NG2+ cells in the optic nerve raises the intriguing possibility that these cells could be the tumor-initiating cells, as has been suggested for adult glioma. In this report, we used a combination of complementary in vitro and novel GEM strains in vivo to determine whether NG2+ cells could give rise to Nf1 optic glioma. First, we show that Nf1 inactivation results in a cell-autonomous increase in GFAP+, but not NG2+, cell proliferation in vitro. Second, similar to the GFAP-Cre transgenic strain that drives Nf1 optic gliomagenesis, NG2-expressing cells also give rise to all three macroglial lineages in vivo. Third, in contrast to the GFAP-Cre strain, Nf1 gene inactivation in NG2+ cells is not sufficient for optic gliomagenesis in vivo. Collectively, these data demonstrate that NG2+ cells are not the cell of origin for mouse optic glioma and support a model in which gliomagenesis requires Nf1 loss in specific neuroglial progenitors during embryogenesis.
PMCID: PMC3874418  PMID: 23318450
genetically-engineered mice; NG2; optic glioma; neurofibromatosis type 1
6.  Optic Nerve Dysfunction in a Mouse Model of Neurofibromatosis-1 Optic Glioma 
Individuals with neurofibromatosis type 1 (NF1) are prone to develop optic pathway gliomas that can result in significant visual impairment. To explore the cellular basis for the reduced visual function resulting from optic glioma formation, we employed a genetically engineered mouse model of Nf1 optic glioma (Nf1+/−GFAPCKO mice). We performed multi-modal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6 weeks of age, prior to obvious glioma formation, Nf1+/−GFAPCKO mice had decreased visual evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/−GFAPCKO mice exhibited pronounced optic nerve axonopathy and apoptosis of neurons in the retinal ganglion cell layer. Magnetic resonance diffusion tensor imaging showed a progressive increase in radial diffusivity between 6 weeks and 6 months of age in the optic nerve proximal to the tumor indicating ongoing deterioration of axons. These data suggest that optic glioma formation results in early axonal disorganization and damage that culminates in retinal ganglion cell death. The Nf1+/−GFAPCKO mice provide a useful model for defining mechanisms of visual abnormalities in children with NF1 and lay the foundations for future interventional studies aimed at reducing visual loss.
PMCID: PMC2746323  PMID: 19525901
Apoptosis; Magnetic resonance imaging; Neurofibromatosis-1; Optic pathway glioma; Retinal ganglion cell; Visual evoked potential
7.  Ultrastructural Characterization of the Optic Pathway in a Mouse Model of Neurofibromatosis-1 Optic Glioma 
Neuroscience  2010;170(1):178-188.
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+/−, Nf1GFAPCKO (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.
PMCID: PMC2926211  PMID: 20600672
neurofibromatosis-1; optic glioma; astrocyte; retinal ganglion cell; microglial cell; electron microscope tomography
8.  Neurofibromatosis-1 Heterozygosity Increases Microglia in a Spatially- and Temporally-Restricted Pattern Relevant to Mouse Optic Glioma Formation and Growth 
While carcinogenesis requires the acquisition of driver mutations in progenitor cells, tumor growth and progression is heavily influenced by the local microenvironment. Previous studies from our laboratory have employed Neurofibromatosis-1 (NF1) genetically engineered mice to characterize the role of stromal cells and signals to optic glioma formation and growth. Previously, we have shown that Nf1+/- microglia in the tumor microenvironment are critical cellular determinants of optic glioma proliferation. To define the role of microglia in tumor formation and maintenance further, we employed CD11b-TK mice, in which resident brain microglia (CD11b+, CD68+, Iba1+, CD45low cells) can be ablated at specific times following ganciclovir (GCV) administration. GCV-mediated microglia reduction reduced Nf1 optic glioma proliferation during both tumor maintenance and tumor development. We identified the developmental window during which microglia are increased in the Nf1+/- optic nerve and demonstrated that this accumulation reflected delayed microglia dispersion. The increase in microglia in the Nf1+/- optic nerve was associated with reduced expression of the chemokine receptor, CX3CR1, such that reduced Cx3cr1 expression in Cx3cr1-GFP heterozygous knockout mice led to a similar increase in optic nerve microglia. These results establish a critical role for microglia in the development and maintenance of Nf1 optic glioma.
PMCID: PMC3044783  PMID: 21157378
Astrocytoma; Chemokine; Fractalkine receptor; Microenvironment; Optic glioma; Stroma
9.  Retinal Nerve Fiber Layer Thickness in Children with Optic Pathway Gliomas 
American journal of ophthalmology  2011;151(3):542-549.e2.
To determine the relation of high-contrast visual acuity (VA) and low-contrast letter acuity with retinal nerve fiber layer (RNFL) thickness in children with optic pathway gliomas.
Cross-sectional convenience sample, with prospective data collection, from a tertiary care children’s hospital of patients with optic pathway gliomas associated with Neurofibromatosis type 1, sporadic OPG and Neurofibromatosis type 1 without OPG.
Patients performed best corrected VA testing using surrounded HOTV optotypes and low-contrast letter acuity (5%, 2.5% and 1.25% low contrast Sloan letter charts). Mean RNFL thickness (microns) was measured by a Stratus optical coherence tomography (Carl Zeiss Meditec, Dublin, CA) using the fast RNFL thickness protocol. Eyes were classified as having abnormal vision if they had high-contrast VA > 0.1 logMAR or visual field loss. The association of subject age, glioma location and RNFL thickness with both VA and low-contrast letter acuity scores was evaluated by one-way analysis of variance and linear regression, using the generalized estimating equation approach to account for within-patient intereye correlations.
Eighty-nine eyes of patients with optic pathway gliomas were included and 41 were classified as having abnormal VA or visual field loss. Reduced RNFL thickness was significantly associated with higher logMAR scores for both VA (P < 0.001) and all low-contrast letter acuity charts (P < 0.001) when accounting for age and glioma location.
Eyes of most children with optic pathway gliomas and decreased RNFL thickness had abnormal visual acuity or visual field loss.
PMCID: PMC3053008  PMID: 21232732
10.  A case of neurofibromatosis 1 presenting with optic pathway glioma with an early onset and an aggressive course 
Indian Journal of Ophthalmology  2008;56(2):161-162.
Optic pathway glioma associated with neurofibromatosis 1 has a classically indolent course. However, involvement of the optic radiations is relatively rare and is associated with a more aggressive course. A three-year-old girl presented with strabismus and loss of vision in the left eye with relative afferent pupillary defect and optic disc pallor. She had multiple café au lait spots. Visually evoked potential was suggestive of an optic nerve conduction defect and magnetic resonance imaging of the brain was suggestive of an optic pathway glioma involving the optic nerves, the optic chiasma and the optic tracts. The optic radiations and the dentate nuclei had hamartomas. Optic nerve biopsy confirmed pilocytic astrocytoma. Radical radiotherapy under general anesthesia was subsequently given. This case report aims to highlight the involvement of the optic radiations and the unusually aggressive clinical course in this case.
PMCID: PMC2636080  PMID: 18292634
Glioma; neurofibromatosis 1; optic radiations
11.  Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation 
Development (Cambridge, England)  2005;132(24):5577-5588.
The gene responsible for neurofibromatosis type 1 (NF1) encodes a tumor suppressor that functions as a negative regulator of the Ras proto-oncogene. Individuals with germline mutations in NF1 are predisposed to the development of benign and malignant tumors of the peripheral and central nervous system (CNS). Children with this disease suffer a high incidence of optic gliomas, a benign but potentially debilitating tumor of the optic nerve; and an increased incidence of malignant astrocytoma, reactive astrogliosis and intellectual deficits. In the present study, we have sought insight into the molecular and cellular basis of NF1-associated CNS pathologies. We show that mice genetically engineered to lack NF1 in CNS exhibit a variety of defects in glial cells. Primary among these is a developmental defect resulting in global reactive astrogliosis in the adult brain and increased proliferation of glial progenitor cells leading to enlarged optic nerves. As a consequence, all of the mutant optic nerves develop hyperplastic lesions, some of which progress to optic pathway gliomas. These data point to hyperproliferative glial progenitors as the source of the optic tumors and provide a genetic model for NF1-associated astrogliosis and optic glioma.
PMCID: PMC2760350  PMID: 16314489
Neurofibromatosis type 1; Optic glioma; Glial progenitor; Astrocyte; Tumor suppressor gene; Mouse
12.  Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation 
Annals of neurology  2013;73(2):303-308.
While traditional models of carcinogenesis have largely focused on neoplastic cells, converging data have revealed the importance of non-neoplastic stromal cells in influencing tumor growth and progression. Leveraging a genetically-engineered mouse model of NF1-associated optic glioma, we now demonstrate that stromal microglia express the CX3CR1 chemokine receptor, such that reduced CX3CR1 expression decreases optic nerve microglia. Moreover, genetic reduction of Cx3cr1 expression in Nf1 optic glioma mice delays optic glioma formation. Coupled with previous findings demonstrating that microglia maintain optic glioma growth, these new findings provide a strong preclinical rationale for the development of future stroma-directed glioma therapies in children.
PMCID: PMC3608848  PMID: 23424002
genetically-engineered mice; monocyte; astrocytoma; brain tumor; fractalkine
13.  Defective Cyclic AMP Generation Underlies the Sensitivity of Central Nervous System Neurons to Neurofibromatosis-1 Heterozygosity 
Individuals with the Neurofibromatosis-1 (NF1) inherited cancer syndrome exhibit neuronal dysfunction that predominantly affects the central nervous system (CNS). In this report, we demonstrate a unique vulnerability of CNS neurons, but not peripheral nervous system (PNS) neurons, to reduced Nf1 gene expression. Unlike dorsal root ganglion neurons, Nf1 heterozygous (Nf1+/−) hippocampal and retinal ganglion cell (RGC) neurons have decreased growth cone areas and neurite lengths, and increased apoptosis compared to their wild-type counterparts. These abnormal Nf1+/− CNS neuronal phenotypes do not reflect Ras pathway hyperactivation, but rather result from impaired neurofibromin-mediated cAMP generation. In this regard, elevating cAMP levels with forskolin or rolipram treatment, but not MEK or PI3-K inhibition, reverses these abnormalities to wild-type levels in vitro. In addition, Nf1+/− CNS, but not PNS, neurons exhibit increased apoptosis in response to excitotoxic or oxidative stress in vitro. Since children with NF1-associated optic gliomas often develop visual loss and Nf1 genetically-engineered mice with optic glioma exhibit RGC neuronal apoptosis in vivo, we further demonstrate that RGC apoptosis resulting from optic glioma in Nf1 genetically-engineered mice is attenuated by rolipram treatment in vivo. Similar to optic glioma-induced RGC apoptosis, the increased RGC neuronal death in Nf1+/− mice following optic nerve crush injury is also attenuated by rolipram treatment in vivo. Together, these findings establish a distinctive role for neurofibromin in CNS neurons with respect to vulnerability to injury, define a CNS-specific neurofibromin intracellular signaling pathway responsible for neuronal survival, and lay the foundation for future neuroprotective glioma treatment approaches.
PMCID: PMC2864934  PMID: 20410111
Neurofibromin; cAMP; neuronal survival; optic glioma; CNS neurons; neurite extension
14.  Optic Nerve Sheath Meningioma in the First Decade of Life: Case Report and Review of the Literature 
Case Reports in Ophthalmology  2012;3(2):270-276.
Tumors of the optic nerve are mostly either optic nerve gliomas or optic nerve sheath meningiomas (ONSMs). While gliomas occur in children, most meningiomas are slow-growing tumors affecting middle-aged individuals with progressive visual loss, proptosis, disc edema and optociliary veins on fundus examination. ONSMs are extremely rare in children, with only 14 cases reported in children under the age of 10 years. The purpose of this study is to describe an additional case and review clinical, radiologic and histopathological findings that can help differentiate such tumors in children and allow an early and accurate diagnosis.
Case Report
An 8-year-old girl had a 2-year history of progressive proptosis and total visual loss on the right side. A computed tomography scan revealed a well-defined intraconal mass with perioptic calcification. Magnetic resonance imaging showed a tumor surrounding the optic nerve and extending intracranially, with enhancement following gadolinium injection. The patient was submitted to fronto-orbital craniotomy for complete tumor excision. Histological studies identified the neoplasm as ONSM.
Though unusual, ONSMs may occur in children and, in these cases, present a much more aggressive behavior than in adults. ONSM should therefore be differentiated from optic glioma in children because of its aggressive behavior and need for different treatment modalities.
PMCID: PMC3457045  PMID: 23071466
Optic nerve neoplasms; Benign optic nerve sheath neoplasm; Meningioma
15.  CyberKnife® enhanced conventionally fractionated chemoradiation for high grade glioma in close proximity to critical structures 
With conventional radiation technique alone, it is difficult to deliver radical treatment (≥ 60 Gy) to gliomas that are close to critical structures without incurring the risk of late radiation induced complications. Temozolomide-related improvements in high-grade glioma survival have placed a higher premium on optimal radiation therapy delivery. We investigated the safety and efficacy of utilizing highly conformal and precise CyberKnife radiotherapy to enhance conventional radiotherapy in the treatment of high grade glioma.
Between January 2002 and January 2009, 24 patients with good performance status and high-grade gliomas in close proximity to critical structures (i.e. eyes, optic nerves, optic chiasm and brainstem) were treated with the CyberKnife. All patients received conventional radiation therapy following tumor resection, with a median dose of 50 Gy (range: 40 - 50.4 Gy). Subsequently, an additional dose of 10 Gy was delivered in 5 successive 2 Gy daily fractions utilizing the CyberKnife® image-guided radiosurgical system. The majority of patients (88%) received concurrent and/or adjuvant Temozolmide.
During CyberKnife treatments, the mean number of radiation beams utilized was 173 and the mean number of verification images was 58. Among the 24 patients, the mean clinical treatment volume was 174 cc, the mean prescription isodose line was 73% and the mean percent target coverage was 94%. At a median follow-up of 23 months for the glioblastoma multiforme cohort, the median survival was 18 months and the two-year survival rate was 37%. At a median follow-up of 63 months for the anaplastic glioma cohort, the median survival has not been reached and the 4-year survival rate was 71%. There have been no severe late complications referable to this radiation regimen in these patients.
We utilized fractionated CyberKnife radiotherapy as an adjunct to conventional radiation to improve the targeting accuracy of high-grade glioma radiation treatment. This technique was safe, effective and allowed for optimal dose-delivery in our patients. The value of image-guided radiation therapy for the treatment of high-grade gliomas deserves further study.
PMCID: PMC2891601  PMID: 20534128
16.  Optic nerve glioma: A great mimicker 
Arachnoid proliferation, although rare, is known to occur in association with optic gliomas. However, chondroid and chordoid metaplasia has not been reported previously.
Case Description:
A 27-year-old male presented with progressive, painless loss of vision in right eye, associated with vomiting and headache for one and a half months. Computed tomography (CT) scan revealed a contrast enhancing mass arising from planum sphenoidale. Perioperative findings showed the tumor adherent to the right optic nerve and attached to basal dura and falx. A clinical impression of an intradural, optic nerve sheath meningioma was made. Histopathological examination revealed a glial tumor with adjacent areas displaying marked fibroblastic and arachnoid cell proliferation with chondroid as well as chordoid differentiation along with myxoid change and dense collagenisation. Reticulin stain, immunochemistry with glial fibrillary acid protein (GFAP), epithelial membrane antigen (EMA), and S-100 helped to arrive at the final diagnosis of optic glioma displaying exuberant arachnoid proliferation with cartilaginous metaplasia.
We report a case of optic nerve glioma displaying extensive arachnoid proliferation, chordoid, and cartilaginous metaplasia, which mimicked chondrosarcoma or chordoid meningioma, posing a diagnostic dilemma. A clinical feedback, simple reticulin stain, and GFAP staining is of immense value in such cases to arrive at the correct diagnosis.
PMCID: PMC3927089  PMID: 24575324
Arachnoid hyperplasia; chondroid; chordoid; glioma; optic nerve
17.  BRAF Duplications and MAPK Pathway Activation Are Frequent in Gliomas of the Optic Nerve Proper 
Optic pathway gliomas represent a specific subtype of astrocytoma with unique clinicopathologic and biological properties but studies of tumors in the optic nerve proper have been hampered by limited tissue availability. We analyzed optic nerve gliomas of 59 patients (median age 9 years, range = 3 months to 66 years; 33 female; 26 male) using formalin-fixed paraffin embedded material in tissue microarrays. Seven patients had the clinical diagnosis of neurofibromatosis type 1 (NF1). Fluorescence in situ hybridization studies were performed for BRAF, PTEN, CDKN2A (p16), and NF1. Immunohistochemistry was performed for glial fibrillary acidic protein, phospho-ERK and mutant IDH1R132H protein. BRAF duplication was present in 11 (of 15) (73%) evaluable tumors including 1 NF1 patient (1 of 4 tested, 25%). The single tumor lacking BRAF duplication or NF1-association had histologic features of a ganglioglioma. Conversely, heterozygous PTEN deletions were present in 2 (of 25) (8%) evaluable cases, one of which was BRAF-duplicated and the other NF1-associated. CDKN2A and NF1 deletions were absent in all tumors tested. Phospho-ERK immunoreactivity was present in 55 (of 57) (96%) tumors, and was mostly strong and diffuse (80%). Only 1 case (of 53) expressed IDH1R132H. Thus, optic nerve gliomas demonstrated molecular alterations typical of pilocytic astrocytomas, including the universal presence of either BRAF duplication or NF1-association and common MAPK pathway activation, but very rare mutant IDH1 expression.
PMCID: PMC3429698  PMID: 22892521
BRAF; Fluorescence in situ hybridization (FISH); Glioma; MAPK; Neurofibromatosis; Optic nerve; Pilocytic astrocytoma
18.  High resolution magnetic resonance imaging of the anterior visual pathway in patients with optic neuropathies using fast spin echo and phased array local coils. 
High resolution MRI of the anterior visual pathways was evaluated using frequency selective fat suppressed fast spin echo (FSE) sequences in conjunction with phased array local coils in patients with optic neuropathies. Fifteen normal controls and 57 patients were examined. Coronal T2 weighted fat suppressed FSE images were obtained in 11 minutes with an in plane resolution of 0.39 x 0.39 mm. The optic nerve and its sheath containing CSF were clearly differentiated. Central retinal vessels were often visible. In demyelinating optic neuritis and in anterior ischaemic optic neuropathy high signal within the nerve was readily delineated. Meningiomas and gliomas involving the optic nerve were precisely visualised both in the orbit and intracranially. Extrinsic compression of the optic nerves was readily visualised in carotid artery ectasia and dysthyroid eye disease. Enlarged subarachnoid spaces around the optic nerves were demonstrated in benign intracranial hypertension. High resolution MRI of the anterior visual pathway represents an advance in the diagnosis and management of patients presenting with optic neuropathy.
PMCID: PMC1073486  PMID: 7745403
19.  Arachnoid hyperplasia in optic nerve glioma: confusion with orbital meningioma. 
A case is reported of an optic nerve glioma with a marked degree of arachnoid hyperplasia which was initially diagnosed as an optic nerve meningioma. Hyperplasia of the arachnoid was also the underlying cause for expansion of the optic canal. The relationship between arachnoid hyperplasia in optic nerve glioma and meningioma of the optic nerve sheath in childhood is discussed.
PMCID: PMC1043565  PMID: 486377
20.  An 80-Year Experience with Optic Nerve Glioma Cases at the Armed Forces Institute of Pathology: Evolution from Museum to Molecular Evaluation Suggests Possibe Interventions in the Cellular Senescence and Microglial Pathways (An American Ophthalmological Society Thesis) 
To determine whether p16, a molecular marker of cellular senescence, and CD68, a microglial marker, are detectible in optic nerve glioma tissue stored for decades, thus providing potential targets for pharmacologic intervention.
Cases were retrieved from the Armed Forces Institute of Pathology Registry of Ophthalmic Pathology. Clinical information was tabulated. In specimens with sufficient tissue, a tissue microarray was constructed to conduct molecular studies.
Ninety-two cases were included: gender distribution was in a ratio of one male to 1.6 females, and age range was 2 months to 50 years (average age, 10.8 years). Neurofibromatosis type 1 was identified in 10 cases (10.8%). The majority presented with decreased vision and exophthalmos. Forty-eight cases were studied by a tissue microarray construction. Glial fibrillary acidic protein, a control for immunoreactivity, was positive in 46 cases (96%). Immunoreactivity for p16 protein was seen in 36 cases (75%) and CD68-positive cells in 34 (71%). Limitations include referral bias, limited clinical information, limited amount of tissue, and extended period of tissue preservation.
Optic nerve glioma is a tumor of the visual axis in young individuals, which is generally indolent but with a variable clinical course. Traditional histopathologic techniques have not been reliably predictive of clinical course. This microarray contains tumors with representative demographic, clinical, and histologic characteristics for optic nerve glioma. Immunoreactivity for p16 protein and CD68 is positive in the majority. These findings suggest a possible explanation for the variable clinical course and identify therapeutic targets in the cell senescence and microglial pathways.
PMCID: PMC4234453  PMID: 25411512
21.  Optic nerve glioma and phaeochromocytoma associated with von Recklinghausen's disease: A case report. 
A 32-year-old woman who died suddenly during pregnancy as a result of an adrenal phaeochromocytoma also suffered from von Recklinghausen's disease. 21 years earlier she had an optic nerve glioma successfully removed. The association between von Reckinghausen's disease and optic nerve glioma/phaeochromocytoma is well established. So far as is known, the present case is the first ever published with the triad: von Recklinghausen's disease, optic nerve glioma, and phaeochromocytoma.
PMCID: PMC1042923  PMID: 403930
22.  Notch3 Activation Promotes Invasive Glioma Formation in a Tissue Site-Specific Manner 
Cancer research  2011;71(3):1115-1125.
While Notch signaling has been widely implicated in neoplastic growth, direct evidence for in vivo initiation of neoplasia by the pathway in murine models has been limited to tumors of lymphoid, breast, and choroid plexus cells. To examine tumorigenic potential in the eye and brain, we injected retroviruses encoding activated forms of Notch1, Notch2, or Notch3 into embryonic mice. Interestingly, the majority of animals infected with active Notch3 developed proliferative lesions comprised of pigmented ocular choroid cells, retinal and optic nerve glia, and lens epithelium. Notch3-induced lesions in the choroid, retina, and optic nerve were capable of invading adjacent tissues, suggesting that they were malignant tumors. While Notch3 activation induced choroidal tumors in up to 67% of eyes, Notch1 or Notch2 activation never resulted in such tumors. Active forms of Notch1 and Notch2 did generate a few small proliferative glial nodules in the retina and optic nerve, while Notch3 was ten-fold more efficient at generating growths, many of which were large invasive gliomas. Expression of active Notch1/Notch3 chimeric receptors implicated the RAM (RBPjk-association molecule) and transactivation domains (TAD) of Notch3 in generating choroidal and glial tumors, respectively. In contrast to our findings in the optic nerve and retina, introduction of active Notch receptors, including Notch3, into the brain never caused glial tumors. Our results highlight the differential ability of Notch receptor paralogs to initiate malignant tumor formation, and suggest that glial precursors of the optic nerve, but not the brain, are susceptible to transformation by Notch3.
PMCID: PMC3076023  PMID: 21245095
Notch signaling; Notch3; astrocyte; optic nerve; glioma
23.  Rare Case of Optic Pathway Glioma with Extensive Intra-Ocular Involvement in a Child with Neurofibromatosis Type 1 
We present a case of a 3-year-old girl with a positive family history of neurofibromatosis type-1 (NF1) presented with best corrected visual acuity of 20/40 in the right eye and <20/400 in the left eye. External ocular examination revealed left eye proptosis of 3 mm, grade II left relative afferent pupillary defect and full range of ocular motility with no strabismus. Slit lamp examination revealed iris lisch nodules bilaterally. Dilated fundus examination of the right eye was normal. Left eye disclosed a large mass extending from the optic nerve head, with associated subretinal fluid. There was neovascularization at the optic disc as well as a superior retinal hemorrhage. Computed tomography of brain/orbits showed an enlarged left optic nerve with a large mass at the optic nerve head, with no evidence of calcification. In addition, a large left optic pathway glioma (OPG), multiple hamartomas within the brain and a smaller low-grade right OPG was also reported. The remarkable feature of our case is the rare intraocular optic nerve involvement of the OPG. Early and regular ophthalmological assessment of all NF1 suspect/confirmed cases is of paramount importance in order to detect OPG early, resulting in timely intervention and salvage of vision.
PMCID: PMC4302466  PMID: 25624686
Genetic Disease; Optic Nerve; Tumors
24.  Membrane-type 1 Matrix Metalloprotease (MT1-MMP) Enables Invasive Migration of Glioma Cells in Central Nervous System White Matter  
The Journal of Cell Biology  1999;144(2):373-384.
Invasive glioma cells migrate preferentially along central nervous system (CNS) white matter fiber tracts irrespective of the fact that CNS myelin contains proteins that inhibit cell migration and neurite outgrowth. Previous work has demonstrated that to migrate on a myelin substrate and to overcome its inhibitory effect, rat C6 and human glioblastoma cells require a membrane-bound metalloproteolytic activity (C6-MP) which shares several biochemical and pharmacological characteristics with MT1-MMP. We show now that MT1-MMP is expressed on the surface of rat C6 glioblastoma cells and is coenriched with C6-MP activity. Immunodepletion of C6-MP activity is achieved with an anti–MT1-MMP antibody. These data suggest that MT1-MMP and the C6-MP are closely related or identical. When mouse 3T3 fibroblasts were transfected with MT1-MMP they acquired the ability to spread and migrate on the nonpermissive myelin substrate and to infiltrate into adult rat optic nerve explants. MT1-MMP–transfected fibroblasts and C6 glioma cells were able to digest bNI-220, one of the most potent CNS myelin inhibitory proteins. Plasma membranes of both MT1-MMP–transfected fibroblasts and C6 glioma cells inactivated inhibitory myelin extracts, and this activity was sensitive to the same protease inhibitors. Interestingly, pretreatment of CNS myelin with gelatinase A/MMP-2 could not inactivate its inhibitory property. These data imply an important role of MT1-MMP in spreading and migration of glioma cells on white matter constituents in vitro and point to a function of MT1-MMP in the invasive behavior of malignant gliomas in the CNS in vivo.
PMCID: PMC2132902  PMID: 9922462
MT1-MMP; diffuse astrocytoma; invasion; central nervous system; metalloprotease
25.  Comparative Characterization of the Human and Mouse Third Ventricle Germinal Zones 
Recent evidence indicates differences in neural stem cell (NSC) biology in different brain regions. For example, we demonstrated that neurofibromatosis-1 (NF1) tumor suppressor gene inactivation leads to increased NSC proliferation and gliogenesis in the optic chiasm and brainstem, but not in the cerebral cortex. The differential effect of Nf1 inactivation in the optic nerve and brainstem (in which gliomas commonly form in children with NF1) vs. the cortex (in which gliomas rarely develop) suggests the existence of distinct ventricular zones for gliomagenesis in children and adults. Here, we characterized the third ventricle subventricular zone (tv-SVZ) in young and adult mice and human brains. In children but not adult humans the tv-SVZ contains nestin-positive, glial fibrillary acidic protein (GFAP)-positive, brain fatty acid binding protein-positive and sox2-positive cells with radial processes and prominent cilia. In contrast, the tv-SVZ in young mice contains sox2-positive progenitor cells and ciliated ependymal lining cells, but lacks GFAP-positive, nestin-positive radial glia. As in the lateral ventricle SVZ (lv-SVZ), proliferation in the human and murine tv-SVZ decreases with age. The tv-SVZ in adult mice lacks the hypocellular subventricular zone observed in adult human specimens. Collectively, these data indicate the existence of a subventricular zone relevant to our understanding of glioma formation in children and will assist interpretation of genetically engineered mouse glioma models.
PMCID: PMC3127083  PMID: 21666496
Germinal zone; Third ventricle

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